Oms-Ops-2001 DM

A MODEL
REGULATORY PROGRAM
FOR MEDICAL DEVICES:
AN INTERNATIONAL GUIDE
ESSENTIAL DRUGS AND TECHNOLOGY PROGRAM

DIVISION OF HEALTH SYSTEMS AND SERVICES DEVELOPMENT
PAN AMERICAN HEALTH ORGANIZATION
Pan American Sanitary Bureau, Regional Office of the
WORLD HEALTH ORGANIZATION
in cooperation with
UNITED STATES FOOD AND DRUG ADMINISTRATION
A MODEL
REGULATORY PROGRAM
FOR MEDICAL DEVICES:
AN INTERNATIONAL GUIDE
Author: Robert C. Eccleston
Editor: Antonio Hernández
April 2001
ESSENTIAL DRUGS AND TECHNOLOGY PROGRAM

DIVISION OF HEALTH SYSTEMS AND SERVICES DEVELOPMENT
PAN AMERICAN HEALTH ORGANIZATION
Pan American Sanitary Bureau, Regional Office of the
WORLD HEALTH ORGANIZATION
in cooperation with
UNITED STATES FOOD AND DRUG ADMINISTRATION
i
A Model Regulatory Program for Medical Devices: An International Guide
PAHO Cataloguing-in-Publication
Pan American Health Organization
A Model Regulatory Program For Medical Devices: An International Guide
Washington, D.C. PAHO, ©2001. 72p.
ISBN 92 75 12345 4
I. Title II. Author
1. EQUIPMENT AND SUPPLIES
2. MEDICAL TECHNOLOGY
3. CONSUMER PRODUCT SAFETY
4. POSTMARKETING PRODUCT SURVEILLANCE
5. LABORATORY EQUIPMENT
NLM W26.P187 2000
ISBN 92 75 12345 4
© Pan American Health Organization, 2001

Publications of the Pan American Health Organization enjoy copyright protection in accordance with
the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The Pan
American Health Organization welcomes requests for permission to reproduce or translate its publica-
tions in part or in full. Applications or inquiries should be addressed to the Division of Health Systems
and Services Development, Essential Drugs and Technology Program, Pan American Health Organiza-
tion/World Health Organization, Washington, D.C., which will be glad to provide the latest informa-
tion on any changes made to the text, plans for new editions, and reprints and translations already
available.
The designations employed and the presentation of the material in this publication do not imply the
expression of any opinion whatsoever on the part of the Secretariat of the Pan American Health Orga-
nization concerning the legal status of any country, city, or area or its authorities, or concerning the
delimination of its frontiers or boundaries.
The mention of specific companies or of certain manufacturers’ products does not imply that they are
endorsed or recommended by the Pan American Health Organization/World Health Organization in
preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the
names of proprietary products are distinguished in PAHO publications by initial capital letters.
Design and layout: Matilde Cresswell
ii
FOREWORD
“WHO’s efforts to improve health and quality of life are grounded in the
firm belief that in order to bring about the necessary changes, health poli-
cies must reach beyond the health sector, while remaining rooted in the
health-for-all principles of primary health care. Health is becoming a cen-
tral political, social and economic issue in all countries, and health con-
cerns must therefore be taken up at the highest political level and given due
consideration in all public policies.”
The World Health Report, 1995
Maintaining and improving human health are noble goals. As the world ush-
ers in a new millennium, these dual goals are more achievable than at any time
in our history given the advent of medical technology. Although medical tech-
nology has emerged as an integral part of health care, it poses a number of unique
challenges. Foremost among these challenges is assuring that medical devices,
like human drugs and vaccines, are produced properly and are used judiciously
and safely so that patients can reap the benefits of mankind’s miraculous inven-
tions.
As technologies become more complex, the role of medical devices in health
care is constantly being re-defined, as is the role of governmental public health
bodies. Some countries around the world have substantial experience in regu-
lating the full gamut of medical device research, development, manufacturing,
distribution and use. Others have more limited rules that apply only to certain
aspects of devices. Still others have no controls pertaining to medical devices. It
is the latter audience that this document is especially designed to reach.
I commend this document to your attention. Its purpose is to assist you in
deciding what governmental controls, if appropriate, are best suited for your
nation’s health care situation.
I wish to recognize and thank Mr. Robert C. Eccleston, Assistant to the Director
in the U. S. Food and Drug Administration’s Center for Devices and Radiological
Health. Mr. Eccleston authored this document in 1996 as a part of an FDA-
supported consultancy for WHO. He later provided expert assistance to PAHO
officials as they prepared the document for publication.
Dr. Daniel López-Acuña

Director Division of Health Systems
and Services Development
iii
iv
TABLE OF CONTENTS
FOREWORD ........................................................................................................................................ iii
PREFACE .............................................................................................................................................. vii
NOTE TO USERS OF THE GUIDE ........................................................................................................ ix
INTRODUCTION ................................................................................................................................. xi
SECTION I
GUIDING PRINCIPLES AND ESSENTIAL FEATURES OF A REGULATORY PROGRAM FOR MEDICAL DEVICES .............................. 1
SECTION II
A MODULAR APPROACH TO A REGULATORY PROGRAM FOR MEDICAL DEVICES ......................................................... 9
SECTION III
REUSE OF MEDICAL DEVICES ........................................................................................................................ 35
APPENDIX - HUMAN SUBJECTS PROTECTION GUIDELINES AND RULES ................................................................. 43

GLOSSARY .......................................................................................................................................... 63
REFERENCES ....................................................................................................................................... 69
v
vi
PREFACE
In the span of three decades, medical devices—from the most basic to the
most sophisticated—have become an indispensable part of the world’s medical
diagnostic and therapeutic armamentarium. With each passing year, advance-
ments in medical technology make it increasingly imperative for governments to
promulgate laws and regulations or undertake other public health measures to
ensure that maximal benefits are derived from their use while risks to patients
are kept to a minimum.
This document and the model program it offers represent an effort towards
that end. In 1986, the World Health Organization (WHO), the Pan American Health
Organization (PAHO) and the United States Food and Drug Administration (FDA)
co-sponsored an International Conference of Medical Device Regulatory Authori-
ties. The conference’s primary goal was to be a “significant first step towards the
promotion of exchange of information and closer communication and coopera-
tion among countries.” On October 20-22, 1999, PAHO sponsored an expert con-
sultation on medical device regulation with senior representatives from the U.S.
FDA, Health Canada’s Medical Devices Bureau and ECRI, among other organiza-
tions.
This document, which as noted previously was initially written by Mr. Rob-
ert C. Eccleston as an FDA consultant to WHO, has been revised in accordance
with comments received from PAHO Member States and experts from the medi-
cal device field. In addition to Mr. Eccleston, the following professionals from
the U. S. Food and Drug Administration contributed to the final preparations of
this document: Ms. Linda Horton, Ms. Minna Golden, Mr. John Stigi, Mr. Steven
Niedelman, Mr. Larry Spears, Ms. Deb Yoder Blum, Mr. Timothy Ulatowski,
Ms. Christine Nelson, Dr. Jerome Donlon, Mr. Les Weinstein and Mr. Wes
Morgenstern. PAHO expresses appreciation to these persons for their invaluable
assistance.
PAHO also wishes to acknowledge the exemplary work of the Global Harmo-
nization Task Force (GHTF), which is referenced in various locations throughout
this document. In keeping with a Resolution CD42.R10 endorsed in 2000 by the
PAHO 42nd Directive Council supporting and promoting the goals of interna-
tional harmonization of medical device regulatory requirements, this document
identifies key areas where GHTF guidance documents may be used to supple-
ment information provided herein.
The document is designed to give countries in pursuit of regulatory or other
controls for medical devices the guidance and information necessary to estab-
lish programs based on individual needs and capacities. It is not intended to
vii
supplant or usurp any ongoing efforts to regulate medical devices in countries

where WHO and PAHO traditionally have provided consultative assistance. To
the contrary, it is offered as a suggested “blueprint” for countries that have al-
ready decided or may decide in the future to embark upon medical device pro-
grams designed to better safeguard public health.
Mr. Antonio Hernández
Regional Advisor
Health Services Engineering and Maintenance
Essential Drugs and Technology Program
Division of Health Systems and Services Development
viii
NOTE TO USERS OF THE GUIDE
It may be useful at the outset to outline the purpose of this international
program guide on medical devices. Although medical devices are used by pro-
viders of health care throughout the world, relatively few of the world’s commu-
nity of nations have systems in place to assure the safety and efficacy of the wide
variety of products, both in terms of their production and use. In fact, in the vast
majority of countries, medical devices, either imported or domestically produced,
are free of any kind of independent and impartial scrutiny. This leaves health
professionals and patients to fend for themselves in deciding which devices will
perform as intended and which can be used safely and effectively in medical
diagnostic and therapeutic procedures.
This document seeks to help fill this void. For government institutions en-
deavoring to establish medical device programs—regulatory or non-regulatory
—this guide is intended to provide the basic “tools” to complete the task. It also
outlines various issues and options countries should weigh carefully in fashion-
ing programs to insure safe and high quality medical devices. Finally, this docu-
ment serves as an informational resource to assist national officials in obtaining
concrete information on a host of issues relating to medical device regulation.
It should be emphasized that this document is not a textbook on how to
perform technology assessment. Nor is it a tutorial on how to procure medical
devices or a prescription for filling the basic medical equipment needs of any
given country. It does not examine the impact of medical device regulation on
trade, economic development or overall societal costs. Finally, this document
does not offer value judgments on any national regulatory system now in opera-
tion.
Rather, this document should be viewed strictly as a suggested framework
that can be modified in accordance with national policies or laws, as well as any
relevant resource and support structure constraints. It should also be pointed
out that in several locations throughout the report, the terms “regulation” and
“regulatory” are used. While in most contexts these terms have very definite and
somewhat limited meanings, it is intended for the purpose of this document that
they be broadly defined. That is to say, “regulation” encompasses more than
strict requirements mandated by a government body. It includes other public
health measures aimed at ensuring the safety and clinical effectiveness of medi-
cal devices in their broadest context.
The U. S. Food and Drug Administration supports the overall purpose of this
publication and applauds the efforts of the Pan American Health Organization
and World Health Organization to promote implementation of effective national
ix
medical device regulatory systems. However, this general support is not, nor
should it be construed as, a formal endorsement by the agency of any of the
specific material contained herein.
Should you have questions about any of the material provided in this docu-
ment, you are encouraged to contact either of the people listed below.
John F. Stigi
Director, Division of Small Manufacturers,
Consumers and International Affairs
Center for Devices and Radiological Health (HFZ-220)
Food and Drug Administration
1350 Piccard Drive
Rockville, MD 20850
USA
Tel. (301) 443-6597, ext. 124
Fax (301) 443-8818
E-mail: jfs@cdrh.fda.gov
Antonio Hernández
Regional Advisor
Health Services Engeneering and Maintenance
Essential Drugs and Technology Program
Division of Health Systems and Services Development
525 23rd Street, N.W.
Washington, D.C.
USA
Tel. (202) 974-3276
Fax (202) 974-3610
E-mail: 1hernana@paho.org
x
INTRODUCTION
It is a truism that medical technology, in varying degrees, has permeated
health care delivery systems throughout the world. Major advances after World
War II in electronics, computerization, biomaterials and other scientific and tech-
nical fields led to the development of life-saving, life-supporting and other criti-
cal devices at a staggering pace. Indeed, more than 50,000 different types of
devices are now being distributed in world trade. This technological revolution,
which has saved lives and improved the quality of life for millions of people,
continues today and should continue on into the foreseeable future.
This post-war phenomenon theoretically knows no geographic boundaries.
Globally, it is estimated that the market for medical devices is growing steadily at
7 percent (1993 estimate) compared to a 1.2 percent growth rate for the world
economy for the same time period. Expansion of the world market is the particu-
lar result of rapidly-emerging markets in Asia and regions in Latin America. In
these areas alone, the rate of market growth is roughly three to four times higher
than for the United States, Japan and Europe. Nevertheless, the availability of
innovative, safe and clinically effective medical devices to the world’s popula-
tion is not universal. This variability in access to even basic medical technolo-
gies exists from continent to continent, country to country, locale to locale and
population group to population group.
At the same time, the types and levels of regulatory controls to safeguard
consumers from unsafe and ineffective medical devices, if they exist at all, also
vary significantly around the world. While efforts are presently underway among
some industrialized nations with medical device regulatory systems to harmo-
nize their requirements to spur global competitiveness and provide for better
husbandry of scarce regulatory resources, many if not most of the world’s devel-
oping countries have no regulatory requirements for medical devices, whether
imported or produced domestically, to protect their citizens.
This document provides a framework to assist Member States in establishing
regulatory programs for medical devices. Because of the differences in socio-
economic conditions that exist among countries that may pursue device regula-
tory programs and their infrastructural capacities to implement them, the model
program contained in this document is, by necessity, relatively general. It is also
designed in a modular format to give interested nations the flexibility to adapt
those elements of the model that best serve their individual needs and which
they are best able to support.
The hope for this document is that it will serve as a useful guidepost for
nations presently without medical device regulatory systems: in other words, to
xi
equip them with the information necessary to get them started in a positive and
internationally-compatible direction, one that will have beneficial societal im-
pacts and enhance public health and safety. The document is based, although
not totally, on the experiences of industrialized sectors of the world which have
established comprehensive regulatory programs for medical devices. It draws
upon what has worked for those nations so that readers may benefit from their
experiences.
xii
xiii
Guiding Principles and Essential Features of a Regulatory Program for Medical Devices SECTION I
SECTION I
Guiding Principles and
Essential Features of A
Regulatory Program For
Medical Devices
1
2
A. GUIDING PRINCIPLES
Preceding any discussion of what constitutes an effective medical device
regulatory system must be the identification of the goals and guiding principles
of such a program. National regulatory programs for consumer goods, including
medical devices, are driven by a panoply of interests: for example, ensuring pub-
lic safety, promoting trade, encouraging marketplace competition and ensuring
timely availability of and access to state-of-the-art technologies and treatment
modalities.
Although some of these factors may have had a bearing on the formulation of
device regulatory systems now operating in various industrialized nations, the
goal of protecting public health and safety is common to all. It is important to
note, however, that in striving to meet this goal, some trade-offs are inevitable.
Regulatory decision-making in general, as is true for medical devices, must oc-
cur against the backdrop of known risks and benefits.
It is a given that nothing in society is perfectly safe. With medical devices
and many other consumer products, societies must learn to cope with and un-
derstand that some level of risk is not only acceptable but inevitable in order to
realize and reap the benefits of their use.
Absolute safety cannot be guaranteed or ever attained. Nor can any regula-
tory system assure that a product will endure and perform optimally forever or
that effectiveness can be totally assured. In any rational regulatory system, rela-
tive risks must be properly balanced against expected benefits. Judgments must
be made based on cultural norms, economic impacts, effects on the viability of
native businesses, the availability of clinically important products and public
acceptance of the premise that nothing in life is risk-free.
With this said, the following suggested tenets can be used as cornerstones of
an effective medical device regulatory program.
Principle 1
The primary goal is to protect public health and safety.
This is the most fundamental goal, provided the underlying mechanisms re-
flect the kind of public attitudes toward risk and the need for reason and realism
that were discussed previously. Accordingly, a device regulatory program must
be grounded in what is reasonably achievable or, in other words, assuring that
medical devices are regulated in a way that weighs probable benefits to health
against the probable risk of illness or injury.
3
Principle 2
A regulatory system should ensure that valuable new technologies are
made available to the clinical community and to patients and consumers
expeditiously while preventing unsafe or ineffective devices from reaching
the market.
Overzealous regulation can become a barrier to trade and an inhibitor of

technological innovation. It can also be counterproductive in the sense that health
care providers and their patients are deprived of valuable new products or that
access to them is significantly delayed. Thus, it is advisable to construct a device
regulatory system to include mechanisms for establishing thresholds of product
safety and effectiveness. The feature that is common to virtually all currently-
operating national device regulatory systems is the concept of classification which
enables governments to regulate devices on a graduated basis depending upon
the risk potential of individual products.
Principle 3
Regulatory decisions must be based on strong and clear science, free of
external influences and consistent with the directives of law.
Regulation is often at the confluence of competing interests and outside forces.

It involves complex interplays between regulators and regulated entities, each of
whom has different objectives and values, often differing scientific judgments
and varying societal values. Thus, public confidence in government regulation
and in those charged to carry out regulatory programs is of paramount impor-
tance. Faith and trust in government regulation by a nation’s citizenry can be
sustained only if regulatory decisions are based on quality science, a sound ana-
lytical base, and fairness and honesty in dealings with the regulated industry
and the public.
Principle 4
As the guarantor of public health, enforcement of the law must be
vigorously, fairly and uniformly carried out and appropriate regulatory and
legal actions taken against violators.
The effectiveness of any regulatory system with legal underpinnings is af-

fected by the commitment to strong enforcement of the law by those entrusted to
implement the program. Promoters of bogus devices and producers of devices
4
which experience unforeseen failures must be dealt with fairly, but resolutely.
The public rightfully expects that government regulators will take decisive ac-
tion to protect them from dangerous devices as well as from economic and scien-
tific fraud.
Principle 5
Government-prescribed rules and procedures must be clearly articulated
for those who must comply with them.
Achieving a high level of compliance from establishments subject to require-

ments imposed by government bodies can be heavily influenced by the clarity
and openness with which a governing body conveys what is expected. In other
words, the specific rules promulgated by governments should be “transparent.”
Statutory, regulatory and scientific requirements must be clearly stated so indus-
try will be fully aware of what is expected—that is, no “moving targets.” This
will increase assurance among businesses which must deal with government
officials that their dealings will be fair, even-handed and free of bias. Cloaking
requirements in secrecy or leaving device firms to self-interpret government rules
can arouse suspicion of preferential treatment between competitors. It can also
become a barrier to trade because companies, unsure of whether requirements
will be evenly and predictably applied, may be deterred from establishing mar-
kets in a particular country.
Principle 6
Assuring medical device safety entails more than the functioning of the
device itself; it requires oversight of the use of medical devices.
Users of medical devices can have a profound effect on their safe and effec-
tive performance. Unfamiliarity with a certain technology, use of the product for
clinical indications outside the scope of those specified in labeling, and disre-
gard for contraindications are but a few examples of why devices fail despite the
absence of any inherent design or manufacturing defects. It is crucial that expe-
rience gained with medical devices be shared with other users to prevent future
mishaps. Documenting adverse events, with a complementary mechanism for
alerting other users, should be considered essential.
5
Principle 7
Information on product risks must be openly communicated with health
professionals and consumers.
Informing the public, broadly defined, involves conveying in understand-

able terms what the scientific community knows and explaining in cogent terms
the range of uncertainty that remains. When people are treated fairly and hon-
estly and in a manner that respects their ability to make thoughtful, well-rea-
soned decisions, they tend not to overinflate modest risks and react irrationally.
Accuracy and truthfulness in product labeling, advertising, promotion, and in-
teractions with the public will afford government regulators a better chance of
explaining the risks and benefits of medical devices and gain public acceptance
in the process. It will also ensure that manufacturers impart the information
necessary to guide health care providers on the appropriate use of their products
and guard against adverse health and economic impacts arising from the use of
devices with unsubstantiated medical claims.
Principle 8
Countries instituting medical device programs should be cognizant of
ongoing international harmonization efforts so as to preclude regulatory
controls that conflict with actual harmonized rules and guidelines or with
the spirit and goals of international harmonization.
The globalization of the medical device industry has given rise to the insti-
tution of government controls in more and more nations throughout the world in
order to safeguard the health and safety of their individual populations. How-
ever, due to differing laws, regulatory interpretations and implementation ap-
proaches, international commerce has been hindered. Device manufacturers have
become frustrated over having to comply with either conflicting or redundant
marketing requirements. Communications between countries with medical de-
vice programs have also been hampered as a result of differing regulatory pro-
cesses and nomenclature.
As these difficulties have grown, it became apparent that harmonizing de-
vice regulatory requirements on an international level was imperative. This real-
ization served as the catalyst to the formation of a Global Harmonization Task
Force (GHTF) in the early 1990’s, which is endeavoring to unify international
regulatory requirements pertaining to quality systems and audits, premarket evalu-
ation and post-market vigilance and surveillance. PAHO/WHO Member States
that decide to embark upon medical device programs are encouraged to heed the
6
work outputs of the GHTF in order to profit from the experiences of its partici-
pant nations and thereby avoid further proliferation of disparate regulatory re-
gimes for medical devices.
B. ESSENTIAL FEATURES
With any new undertaking, certain basics are critical to success. In existing
device regulatory systems, there are, indisputably, features common to them. All
must be considered by governments interested in regulating medical devices. A
prerequisite to any program is the adoption of a clear legal definition of the term
“medical device” in order to distinguish this commodity from others that are
also subject to regulation (e.g., pharmaceuticals). In terms of an actual program
structure, the features can be grouped into four basic categories. The first two
activities can apply to importer countries as well as those with native medical
device industries. The latter two apply chiefly to countries with domestic pro-
ducers of medical devices.
1. Establishment of a procedure for identifying manufacturers (and oth-

ers) with business operations in the country for which the regulatory
program is being devised, as well as for imported and domestically-pro-
duced products distributed within national borders. This element should
also encompass information on a product’s history to guard against un-
scrupulous marketers of previously-used devices that are intrinsically
defective, have outlived their normal life expectancies and/or have been
inadequately reconditioned for re-sale.
2. Initiation of a system to maintain vigilance over marketed products to
ensure their continued safety and quality, as well as ongoing regulatory
compliance by manufacturers after obtaining market clearance. As an
adjunct, a method for information sharing among users and national
health authorities of similar devices is vital to preventing additional
adverse incidents and their unwanted health effects.
3. Implementation of a broad-based, regularized program of manufac-
turing site inspections and audits to verify corporate conformance with
clearly-defined manufacturing standards and methods for validating qual-
ity assurance in commercial production of devices.
4. Construction of a regulatory system that is risk-based: that is, a system
that stratifies and applies premarket assessment controls based on
the risk (or hazard) potential of a product, as well as the potential for
misuse and the breadth of commercial distribution, known or projected.
7
8
A Modular Approach to a Regulatory Program for Medical Devices SECTION II
SECTION II
A Modular Approach To A
Regulatory Program For
Medical Devices
9
10
A. PROGRAM OVERVIEW
Medical Device Definition
A rudimentary step in establishing a device regulatory system is to clearly
define what is meant by the term “medical device” and to differentiate it from
other products for which a government body may have regulatory oversight re-
sponsibilities. “Medical device” is used by many as an all-encompassing term
that refers to medical technology, medical supplies and medical equipment. The
distinctions between each of these terms is probably less critical than demarcat-
ing devices from drugs. Fundamentally, the difference lies in the mechanism of
action.
In the case of drugs, the product generally is metabolized by the body for
some intended effect. In contrast, devices generally depend on physical interac-
tion (i.e., mechanical, thermal, electrical or other form of non-metabolic action)
to achieve a desired effect.
Devices differ from drugs in other respects not directly relevant to the issue
of legal definition. For example, many devices have a considerably shorter use-
ful life than drugs given the high degree of innovation and constant turnover
due to technological obsolescence. Unlike the drug industry, which (other than
biotechnology) remains relatively static, the device industry is a dynamic one,
with a diversity of products that is unparalleled in comparison to the field of
pharmaceuticals. In turn, this diversity leads to spirited entrepreneurialism, par-
ticularly among small businesses. Thus the composition of the drug industry
vis-a-vis the device industry is vastly different. Because the make-up of the de-
vice industry is far more heterogeneous, with a large proportion of small compa-
nies, special challenges face those tasked with regulating these products.
Generally speaking, devices can also have considerably higher initial pro-
curement costs. Purchasers face the added cost of maintenance of non-dispos-
able devices over their lifespan that can extend for years. A final difference is
that devices are used by a complex network of health professionals, ancillary
health care workers and consumers, whereas drugs are generally prescribed by
doctors, dispensed by pharmacists and self-administered by patients.
These practical distinctions can affect the crafting of a legal definition. Thus
it is suggested that a medical device be thought of as an instrument, apparatus,
machine, implant or in-vitro reagent whose use is intended for the diagnosis of
disease, or for the cure, mitigation, treatment or prevention of disease, or for
affecting the structure or function of the body for some medical purpose. If a
country’s legal system differentiates devices from drugs, the definition should
11
also specify that devices do not achieve any of their intended purposes by means
of chemical action within or on humans and are not dependent on being metabo-
lized to achieve a result.
It should be recognized that the line distinguishing drugs and devices can
sometimes be blurred as discrete products are physically, chemically or other-
wise combined to form a single product or packaged together in order to achieve
a particular clinical outcome. Medicated wound dressings, bone cements with
antibiotics, syringes pre-filled with specific drugs, inhalers for administering
aerosolized drugs and dental composites with fluoride are but a few examples.
Particularly in cases when a government has vested oversight responsibili-
ties for pharmaceuticals, biologicals and medical devices in different organiza-
tional units, questions can arise as to how the finished combination product will
be regulated and by which government entity. Answering these questions can be
based on the primary mode of action of the finished product. This in turn can be
determined by categorizing the combination product in the same way as other
countries that have already cleared the product, or by requiring manufacturers,
importers or others seeking market clearance to provide information that de-
scribes: (1) the product and its known modes of action; (2) the product’s compo-
nents and their individual composition; (3) the manufacturing processes used;
(4) proposed use indications and schedule/duration of use; and (5) dosage and
route of administration.
Market Entry Notification

Overall, a critical baseline requirement of any medical device program, irre-
spective of its complexity, is the acquisition of information about the establish-
ment seeking to commercially distribute a product. Equally important is the avail-
ability of information—particularly for imported devices that may be second or
later generation products which have been refurbished—describing the perfor-
mance history of the product and any individual adverse events or performance
trends associated with its use. These dual objectives can be accomplished by
requiring manufacturers of devices to submit premarket notifications to the na-
tional regulatory body.
One of the main elements of a notification process is the identification of the
establishment seeking to sell or otherwise conduct business within a national
jurisdiction (often referred to as “registration” or “notification”), in addition to
the identification (or “listing”) of the products to be marketed in that jurisdic-
tion. (This is also sometimes referred to as registration, particularly as it applies
to pharmaceuticals.)
12
Up-to-date records on the identity and physical location of manufacturers,

importers and distributors (and perhaps other entities, such as refurbishers and
contract sterilizers), and on their products and site(s) of manufacture enable
government health officials to locate device establishments in the event some
difficulty arises once the product is in commercial use. This is especially cru-
cial in emergency situations when, for example, circumstances involving a de-
fective device require market removal, product correction and/or health alerts to
users. With this information readily available, governments need to also perform
periodic inspections and spot checks to ensure ongoing compliance by indig-
enous producers of medical devices.
Countries that rely on imports as their primary or exclusive source of medi-
cal equipment are also strongly advised to have in place a program that assures
that the necessary steps have been taken to insure device safety, quality and
effectiveness. Some countries require businesses seeking market clearance to
provide descriptive information relating to their clinical performance, past and
present. Requiring this information as a prerequisite to marketing can be a great
asset to government officials entrusted with public health and welfare and/or the
responsibility of procuring medical equipment. Information on patient morbid-
ity and mortality, attributable to the performance of medical devices, as well as
regulatory actions taken by other regulatory bodies as a result of device failures,
can better ensure well-informed decisions before devices are allowed entry into
a national jurisdiction.
A pragmatic variance on this approach is for an importing country to rely
solely on the market approval granted by countries with comprehensive regula-
tory systems. While this can simplify the process, it also places increasingly
heavy burdens on the countries where approval was initially obtained in terms
of producing export certificates or verifying representations made by product
importers. It can also diminish the amount of self-control that an importing country
exercises over the safety and quality of devices crossing its borders.
Countries that require this information may also want to insist that establish-
ments submit annual update notifications as a means for government officials to
monitor the commercial status of businesses operating in their countries, the
volume of devices distributed and how well the products are performing. That
is, have the products caused or been linked to patient deaths, injuries or ill-
nesses? As is customary in some countries, the administrative costs of this noti-
fication activity can be borne by applicants to offset a portion or all of the costs
associated with processing of notifications and storage and maintenance of offi-
cial records. (Other cost-recovery mechanisms are possible.)
13
Post-Market Vigilance
No amount of rigor in any premarketing review process can predict all pos-
sible device failures or problems arising from product misuse. Thus, the ability
to monitor the performance of marketed devices is an essential component of a
device regulatory system. How elaborate a system is for tracking device perfor-
mance, documenting problems and imparting vital information about device-
related incidents with other users is, of course, a function of available resources
and perhaps other local and national considerations.
It is recommended, however, that some surveillance activity be initiated.
This can range from routine gathering of information related to the performance
of individual devices (as well as trend data for generic types of devices) collected
by other government or private organizations to some form of documenting sys-
tem—mandatory or voluntary—that is operated by the regulatory body. Com-
bined with establishment and product information obtained via a premarket
notification procedure, post-market vigilance data can be invaluable in pinpoint-
ing problems and achieving prompt remediation.
Manufacturing Controls,
Inspections Audits and Safety and
Efficacy/Performance Assessment
The final two levels of a device regulatory program, perhaps more than any
other, are ones that must be adapted to the socioeconomic conditions,
infrastructural capacities and unique needs of individual countries. There is a
broad spectrum of available mechanisms for regulating product safety, which
can be selectively adopted, incrementally applied, or instituted en bloc. This
menu of regulatory controls gives countries broad discretion in designing sys-
tems that are best suited for them and the constituencies they represent.
Whichever route a country chooses, it is strongly suggested that some form of
graduated regulation be employed. This can be done using hierarchial, risk-based
regulation, in a manner similar to the processes used by the United States, Euro-
pean Union and others. Alternatively, products can be typecast and arrayed by
generic category, e.g., implantable, invasive, non-invasive, electrical, life-sup-
porting, etc. Regardless of the regulatory route chosen, careful consideration
should be given to the sub-elements that will constitute the operational basis for
14
assessing device safety and efficacy (the term “effectiveness” is also used syn-
onymously in this text). These can include:
• site inspection of manufacturing facilities and the practices used in mass
production of medical devices;
• required manufacturer conformance with national or international con-
sensus standards developed by third parties that address product safety,
quality, effectiveness, performance and sterility of finished devices;
• premarket testing of production devices, either by the regulatory body,
or the manufacturer or an independent testing entity, that demonstrates
conformance with applicable standards and other performance and mar-
keting requirements;
• mandatory premarket evaluation of new devices and market clearance
to attest that safety, effectiveness and performance requirements are met;
• controls under which devices can be marketed: that is, specifications on
the conditions under which devices can be offered for sale, in addition
to who may use particular devices and under what conditions.
B. SPECIFIC PROGRAM COMPONENTS

Recognizing that no regulatory model is wholly adaptable to every situation,
this section offers a broad and more detailed presentation of the critical elements
of a device regulatory program, as summarized previously. The main elements
and specific requirements are presented in a modular format and color-coded to
assist readers in locating the text that corresponds to each of the colored mod-
ules shown on the next page. Modularizing the program is intended to enable
countries to adopt as little or as much as their individual situations dictate.
This flexibility is purposefully offered in light of the fact that some countries
have few or no device producers within their jurisdiction and thus rely on im-
portation as the principal means for acquiring medical products. Under this sce-
nario, more limited requirements may be appropriate. On the other hand, coun-
tries with device manufacturers conducting business operations within their
geographical borders may require a more extensive regime of regulatory con-
trols. Some overlap is unavoidable since the suggested regulatory paradigm is
pyramidal (as depicted later), meaning that some baseline requirements may be
common to both scenarios. Also, depending upon a country’s own needs, re-
quirements can be integrated: that is, features from one module can be combined
with those of another module without, necessarily, the full adoption of both.
15
MODULE IV:
Safety and
Efficacy/Performance
Assessment
MODULE III:
Manufacturing Controls
and Inspections
MODULE II:
MODULE I:
Module I
As discussed previously, one of the entry-level steps in building a medical

device regulatory program should be establishment registration, product listing
and summary information on product performance, collectively referred to as
notification. (A sample notification form is provided on pages 18-19.) This
minimalist approach can be carried out on either a voluntary or mandatory ba-
sis, although requiring the submission of such baseline information will provide
a higher degree of assurance of comprehensive and usable records.
In the case of notification, this requirement can be applied to a number of
different types of establishments that throughout the course of device produc-
tion and distribution can have an impact on the finished product. As a practical
matter, it can be accomplished with relative ease and a minimum of paperwork,
although storage of data should be accomplished, if practicable, using a comput-
erized database. When employing the premarket notification method, it is sug-
gested that the name of establishment, location (including multiple sites) and
identity of an authorized contact person and type of business establishment be
identified. This requirement should apply to a:
• manufacturer (person or business that produces an article that meets
the legal definition of medical device);
16
• distributor, including multiple distributors of the same device (person

or business that receives finished devices from another establishment
for the purpose of offering them for commercial sale);
• importer (person or business that receives devices from foreign manu-
facturers for the purpose of offering them for commercial sale and/or
distribution in the recipient country);
• repackager (person or business that packages finished devices from bulk
or repackages devices made for shipment in multiple containers);
• relabeler (person or business that changes the content of product label-
ing offered by the original manufacturer for distribution under its own
name);
• contract sterilizer (person or business that provides sterilization ser-
vices for another establishment’s devices); and
• refurbisher/remarketer (person or business that assumes ownership of
previously-used devices and reconditions them for re-sale).
In addition, applicants should be required to provide basic information about
the products intended to be sold and distributed. One approach is to group
products into three clusters: active implantables (such as cardiac pacemakers
and implantable infusion pumps); general medical devices (such as wheelchairs,
scalpels and bandages); and in-vitro diagnostics, which could include tests kits
for hepatitis, pregnancy, HIV, etc. Because applicants may have multiple manu-
facturing locations, it is also advised for purposes of traceability to have the site
of manufacture for a particular product identified in the notification.
Notification forms should provide instructions as to where registrants should
direct the information. Countries may also wish to specify timeframes for filing
notifications as a prerequisite for an establishment to initiate operations (for
example, 30 to 60 days prior to commencing a business or commercial activity).
17
S A M P L E
MARKET ENTRY NOTIFICATION
(To be completed by domestic or foreign establishment)
[ INSERT NAME / ADDRESS OF DEVICE IMPORTER COUNTRY ]
SECTION A
ESTABLISHMENT NAME:
ESTABLISHMENT LOCATION (Street Address): CITY:
COUNTRY: ZIP CODE/POSTAL ADDRESS:
AUTHORIZED ESTABLISHMENT CONTACT/POSITION TITLE:
TELEPHONE NO.: FAX NO.: E-MAIL ADDRESS:
ESTABLISHMENT TYPE (Check one):
ORIGINAL EQUIPMENT MANUFACTURER REPACKAGER/RELABELER

REFURBISHER/REMARKETER CONTRACT STERILIZER
DISTRIBUTOR IMPORTER
SECTION B
PRODUCT TYPE (Check one): SITE OF MANUFACTURE:
ACTIVE IMPLANTABLE
GENERAL MEDICAL DEVICE
IN VITRO DIAGNOSTIC
DEVICE IDENTIFICATION (Give name, number, other relevant identifier information):
SECTION C
PRODUCT APPROVAL STATUS (Check more than one if applicable): OFFICIAL USE ONLY
APPROVED BY US FDA APPLICANT ID NO.:

APPROVED BY EUROPEAN AUTHORITY (CE MARK) DATE OF RECEIT:
APPROVED BY [specify nation(s)]: DATE OF APPROVAL/DISAPPROVAL:
18
SECTION D
PRODUCT HISTORY:
HAS THE PRODUCT TO BE SOLD BEEN SUBJECT OF REGULATORY IN THIS OR ANOTHER COUNTRY IN THE LAST YEAR? (IF YES, IDENTIFY COUNTRY)
YES NO
HAS THE PRODUCT TO BE SOLD EVER BEEN THE SUBJECT OF A VOLUNTARY MARKET WITHDRAWAL IN THIS OR ANOTHER COUNTRY? (IF YES,
IDENTIFY COUNTRY) YES NO
HAS THE PRODUCT TO BE SOLD EVER BEEN THE SUBJECT OF A HEALTH ADVISORY? YES NO
PROVIDE A SUMMARY REPORT ON THE PERFORMANCE HISTORY OF THE DEVICE TO BE SOLD (INCLUDE DESCRIPTION OF ANY ADVERSE EVENTS
ATRIBUTED TO THE PRODUCT THAT RESULTED IN COMPLAINTS RECEIVED BY YOUR ESTABLISHMENT FROM USERS AND RELATED REPORTS MADE TO
NATIONAL GOVERNMENTS
NO PROBLEMS REPORTED
PROBLEM(S) REPORTED (SPECIFY NATURE OF PROBLEM(S) AND NUMBER OF ADVERSE REPORTS; ATTACH SUPPLEMENTAL INFORMATION IF
AVAILABLE ON BASELINE DATA FOR PRODUCT SOLD/DISTRIBUTE):
IS THE PRODUCT AN IMPLANTABLE? YES NO
HAS THE PRODUCT BEEN EXPLANTED AND RE-CONDITIONED FOR SALE?YES NO
IF KNOWN, SPECIFY REMAINING PRODUCT LIFE EXPECTANCY: MONTHS YEARS
IF YOU ANSWERED “YES”TO EITHER OF THE PREVIOUS TWO QUESTIONS, ANSWER THE FOLLOWING:
HAS THE PRODUCT BEEN INDEPENDENTLY TESTED FOR CONFORMANCE WITH SAFETY/QUALITY SPECIFICATIONS? YES NO
IS THE MANUFACTURING PROCESS IN COMPLIANCE WITH GOOD MANUFACTURING PRACTICES AND/OR ISO 9001 STANDARDS?
YES NO
SECTION E
I HEREBY CERTIFY THAT THE FOREGOING INFORMATION IS COMPLETE AND FACTUAL. I UNDERSTAND THAT FAILURE TO REPORT ALL REQUIRED
INFORMATION OR SUBMISSION OF FALSE OR MISLEADING INFORMATION IS A CRIMINAL VIOLATION, PUNISHABLE BY FINE OR IMPRISONMENT OR BOTH.
SIGNATURE OF AUTHORIZED ESTABLISHMENT OFFICIAL DATE
19
Module II
For detailed guidance in this area, it is suggested that readers refer to the
following documents prepared and endorsed by the Global Harmonization Task
Force (GHTF), an international consortium of device regulators and manufactur-
ers whose mission is to develop uniform regulatory approaches for use by na-
tional competent authorities.
• Minimum Data Set for Manufacturer Reports to the National
Competent Authority
• Guidance on How to Handle Information Concerning Vigilance
Reporting Related to Medical Devices
• Global Medical Devices Vigilance Report
• National Competent Authority Report Criteria
• Manufacturer Trend Reporting on Post-Market Medical Device
Associated Adverse Events
• Adverse Event Reporting Guidance for the Medical Device
Manufacturer Or Its Authorized Representative
These documents can be obtained by visiting the GHTF Internet Web site:
www.ghtf.org. Once you have accessed the Home Page, click on “GHTF Docu-
ments” and then select “Study Group 2 - Medical Device Vigilance/Post-Market
Surveillance.” The documents listed above can be found in this category. Addi-
tional guidance in this area is expected in the future.
Please note that reference to or use of this material does not represent en-
dorsement of the Pan American Health Organization or the World Health Organi-
zation.
Module III
Manufacturing Controls and Inspections
following documents prepared and endorsed by the Global Harmonization Task
Force (GHTF), an international consortium of medical device regulators and
manufacturers whose mission is to develop uniform regulatory approaches for
use by national competent authorities.
20
• Guidance on Quality Systems for the Design and Manufacture of

Medical Devices
• Design Control Guidance for Medical Device Manufacturers
• Process Validation Guidance for Medical Device Manufacturers
• Guidelines for Regulatory Auditing of Quality Systems of Medical
Device Manufacturers: Part 1 - General Requirements
• Audit Language Requirements
• Training Requirements for Auditors
ments” and then select “Study Group 3 - Quality System Requirements & Guid-
ance” and “Study Group 4 - Auditing.” The documents listed above can be found
in these two categories. Additional guidance in these areas is expected in the
future.
zation.
Module IV
Safety, Efficacy and Performance Assessment
Introduction
Several of the world’s existing device regulatory systems require manufac-
turers to prove the safety, effectiveness and/or performance of their products as a
condition to commercial marketing, in addition to having sufficient information
to guide doctors on the appropriate use of the products. While the standards of
proof may vary from one regulatory system to another, and depending on whether
governmental entities or non-government entities should bear primary responsi-
bility for conducting premarket evaluations, there is general consensus on the
value of having medical treatment theories and technological concepts validated
by controlled scientific experiments before wide-scale use in humans.
One of the foremost decisions a regulatory authority must make in establish-
ing a premarket review program is whether the program should be oriented strictly
to product safety or whether demonstration of clinical effectiveness/performance
should also be a prerequisite to marketing. Under a “safety only” system, a regu-
latory authority would presumably evaluate safety data for a new device derived
21
from laboratory studies. If such studies, for example, show that a device is safe
and can perform its purported medical functions, it would be allowed on the
market. (Some countries treat the efficacy decision as a part of their health care
financing arrangements.)
Under a “safety only” system, device effectiveness would be measured after
marketing occurs through a process of gradual consensus based on accumulated
experience with the product by health professionals and consumers, as well as
evaluations in the medical literature. Under such a program, ineffective devices
would presumably lose their standing in the marketplace, demand would dimin-
ish and, ultimately, the product would cease to be manufactured.
Another school of thought is that device safety is inextricably linked to effec-
tiveness/performance. Since few if any medical devices are absolutely safe, mak-
ing safety judgments involves a benefit-risk decision. In other words, one can-
not ask simply whether a product is safe, but rather whether it is safe enough in
view of the benefits to patients. For example, the benefit of a life-saving device
where no alternative treatment options exist, may outweigh known risks. On the
other hand, the use of a device with minimal benefits might not be justified
unless the corresponding risks are low and well understood.
Admittedly, assessing effectiveness can be a more time-consuming and costly
endeavor. In recent years, the complexity of medical technology and the rising
demand for cost-effectiveness information have contributed to the ever-growing
need for clinical trials as an objective method of scientific inquiry. However,
measuring patient benefits is not an easy undertaking since some patients may
benefit from a particular medical device while others do not. Thus it becomes
important for health care providers who use a device to know what groups of
patients will benefit from it and under what circumstances. Comparison of a
particular device with other available forms of treatment enables health practi-
tioners to make rational decisions about patient management.
Relying on post-market consensus-building to gauge a product’s effective-
ness can have an impact on patient care in two ways. First, before consensus is
reached among health professionals, a significant number of patients may re-
ceive relatively ineffective and potentially dangerous treatments from unproven
devices. In such cases, patients could be deprived of more effective therapies
and scarce health care resources may be expended for ineffective or marginally
effective medical procedures, which exacerbates the resource problem. Second,
the data to establish a consensus may be inadequate, particularly if it comes
from practitioners’ personal experiences. Individual clinicians rarely treat pa-
tients in sufficient numbers and under controlled conditions to be able to detect
and measure adverse effects or assess clinical outcomes among large patient popu-
lations.
22
Assessing Device Safety, Efficacy and Performance

following document prepared and endorsed by the Global Harmonization Task
Force (GHTF), an international consortium of medical device regulators and
manufacturers, whose mission is to develop uniform regulatory approaches for
use by national competent authorities.
Three documents, relevant to this program area, have received endorsement
from the GHTF. They are:
• Essential Principles of Safety and Performance of Medical Devices
• Labelling for Medical Devices
• Role of Standards In the Assessment of Medical Devices
ments” and then select “Study Group 1 - Regulatory Requirements/Premarket
Review.” The documents listed above can be found in this category. Additional
guidance in this area is expected in the future.
zation.
The Principles of Quality Clinical Studies

Should a regulatory authority decide to compel domestic manufacturers to
show evidence of the safety, effectiveness and/or performance of medical de-
vices, a basic understanding of what constitutes quality clinical trials is essen-
tial. The principles of good clinical study design encompass a wide range of
considerations. Among these are the statistical power of a study, number of hu-
man subjects enrolled in the study, protections for study subjects, clearly de-
fined study objectives and endpoints, and controls against bias and error. In a
stepwise fashion, the following generally describes the key elements of a quality
clinical trial.
• A study protocol should state a clear purpose: that is, a hypothesis to be

tested. This is usually phrased as a research question to address the
medical claims being made for the device.
• If the claims for a product are inadequately known or defined, a sponsor
may wish to conduct a pilot or feasibility study on a small population of
patients. This step will allow claims to be identified more clearly; study
23
procedures to be validated; estimates of patient outcomes and variables

that can affect the larger study to be obtained; and safety and effective-
ness endpoints (e.g., patient inclusion/exclusion criteria) to be defined.
• A study design should be capable of testing the stated hypothesis. This
means that issues such as what constitutes success and failure as they
relate to specific study endpoints must be addressed. There must also be
an appropriate control group for comparison and a sample size large
enough to answer the major questions specified in the protocol.
• The study design must also include proper methods to measure the de-
fined endpoints. Comparability is the goal and can be achieved through
such techniques as randomization and masking (or blinding), in addi-
tion to efforts to ensure as close to 100 percent patient follow-up as pos-
sible in both study and control groups.
• Finally, a study protocol should identify the methods of data analysis
that will be used (i.e., statistical tests), and explain any plans to exclude
certain patients from the analyses, any planned sub-group comparisons,
or “pooling” of the data, and which of several endpoints (if applicable)
will be the primary one.
The principles that govern human subjects protection today are found in the
Nuremberg Code, Declaration of Helsinki and Belmont Document, which are
provided in the Appendix (see page 43).
The Nuremberg Code was developed in the late 1940’s for the Nuremberg
military tribunal as standards by which to judge human experimentation. The
Code captures many of what are now relied upon as the basic principles for the
ethical conduct of research involving human subjects: voluntary consent, mini-
mization of risk and harm, favorable risk-to-benefit ratio, qualified researchers
using appropriate research design and freedom of the subject to withdraw at any
time.
The Declaration of Helsinki, prepared by the World Medical Association in
1964 and revised in 1975 and 1989, embraces principles similar to those in the
Nuremberg Code. It distinguishes therapeutic from non-therapeutic research and
recommends that:
• clinical research be conducted in accordance with accepted scientific
methodologies;
• research objectives are balanced against possible risks to subjects; and
• patients enrolled in clinical trials are made fully aware of the risks and
benefits of the procedure and are afforded the opportunity to give in-
formed consent.
24
The Belmont Document was published by the National Commission for the
Protection of Human Subjects of Biomedical and Behavioral Research in 1979.
This document identifies three essential requirements for the ethical conduct of
research involving human subjects:
• respect for persons: recognition of the personal dignity and autonomy
of individuals and special protection for those persons with diminished
autonomy;
• beneficence: an obligation to protect persons from harm by maximizing
anticipated benefits and minimizing possible risks of harm; and
• justice: fairness in distribution of burdens and benefits, often expressed
in terms of treating persons of similar circumstances or characteristics
similarly.
C. LEGISLATIVE MODEL
On the assumption that countries without regulatory controls for medical
devices lack the basic authorizing legislation upon which to construct a pro-
gram, this section provides a template for use by health agencies and legislative
bodies.
Section 1
Definitions
(A) “Product” means any medical device, medical equipment, medical technology
or medical product.
(B) “Medical product” or “medical device” means any article intended for use
in, or actually used in, the diagnosis, treatment or prevention of disease or
other health condition in humans by a health professional or a patient/
consumer.
(C) “Investigational product” means a product that is experimental and has not
yet been accepted for marketing.
(D) (1) “Safety” means the benefit of a product to a patient who is medically
diagnosed or treated with the product outweighs the risk that the product
might cause harm to the patient.
25
(2) “Effectiveness” or “efficacy” means a product can be shown by valid sci-

entific evidence to produce an intended clinical effect in a target popu-
lation.
(3) “Performance” means a product performs as intended and in accordance
with associated labeling and is in conformance with applicable techni-
cal specifications and relevant product standards.
(E) “Person” means individual, partnership, corporation, association, organiza-
tion or health professional.
(F) “Health professional” means any physician, pharmacist, nurse or any other
person who delivers health care.
(G) “Facility” means any factory, warehouse, store, pharmacy, hospital, carrier,
vessel or any other place where products are manufactured, processed, im-
ported, packed, refurbished, held, distributed, dispensed or sold.
Section 2
General Requirements
(A) A person (including any manufacturer, importer, distributor or refurbisher)

shall not sell any product that is not safe, effective, properly labeled and in
compliance with applicable registration or market approval requirements,
or that otherwise violates the requirements of this law or the regulations
issued under it.
(B) A manufacturer, importer, distributor, repackager/relabeler or refurbisher/
remarketer shall register with the regulatory control authority and shall sub-
mit a list of products for which they are responsible. Registration and listing
information shall be periodically updated as required by the regulatory con-
trol authority. Medical products shall be listed under standardized nomen-
clature as required by the regulatory control authority.
(C) A person shall submit all required applications, documents and other infor-
mation and shall document any voluntary recalls or other corrective action(s)
involving the product to the regulatory control authority.
(D) Any person, other than consumer-patients, who becomes aware that a medi-
cal device may have caused or contributed to an adverse event shall evalu-
ate the information submitted and shall document the event concurrently to
the manufacturer and the regulatory authority.
26
(E) Any manufacturer, importer, distributor or other business entity covered by

this legislation shall establish a procedure for handling device-related com-
plaints from users, as well as for documenting device-related events to the
regulatory control authority.
(F) A person shall not provide any false or misleading information:
(1) to the regulatory authority in applications, documents or other informa-
tion;
(2) in labeling, advertising or other information about a medical device manu-
factured, imported, distributed or otherwise commercialized, or used in
medical practice by that person.
(G) A person in a facility shall permit an inspection by the regulatory authority,
its officers and its employees.
(H) A person shall establish and maintain all records pertaining to medical de-
vices that are required by this law or the regulatory control authority, and
shall make such records available to the regulatory control authority upon
request.
Section 3
Post-Market Vigiliance for Approved Medical Devices
(A) In addition to complying with all other requirements, manufacturers/ spon-

sors of approved medical devices shall comply with whatever requirements
the regulatory control authority may impose at the time market approval is
granted or at any time thereafter, including:
(1) the conduct of additional tests or studies, with acceptable results;
(2) the limitation of a device to prescription use or to other restricted use;
(3) the tracking of a medical device to facilitate product correction or mar-
ket removal in the event of a malfunction or other device failure to which
an adverse impact on human health can be attributed; and
(4) the conduct of post-market surveillance to monitor the performance of a
device in actual use, particularly in cases where long-term performance
could not feasibly be demonstrated during the premarket testing stage.
27
Section 4
Surveillance by Regulatory Control Authority
The regulatory control authority may through its officers and employees:
(1) conduct investigations of persons and medical devices, including in-
spections;
(2) enter a facility for the purpose of inspecting the facility, physical records
and any other materials in the possession of a person who manufactures,
distributes, holds or sells medical devices, and may take photographs,
gather physical evidence and collect product samples;
(3) issue an order requiring that a manufacturer, importer or other business
entity responsible for medical devices submit the results of product safety
and effectiveness testing and, absent such testing, issue an order requir-
ing that such tests be performed and the results submitted to the regula-
tory control authority; and
(4) inspect and copy all records, regardless of their location, that pertain to
medical devices and a facility’s compliance with applicable laws and
regulations.
Section 5
Requirements for Medical Device Manufacturing and Quality Assurance
(A) A manufacturer, processor or packer shall manufacture all medical devices

in conformance with good manufacturing practices and shall not commer-
cially distribute any device that has not been produced in conformity with
such requirements.
(B) A manufacturer, processor or packer shall assure that all medical devices
meet all requisite specifications and product standards prior to offering them
for sale.
(C) A manufacturer, processor or packer shall establish and maintain records
pertaining to all manufacturing, processing and packing activities, as well
as product distribution by lot number.
(D) A person shall not distribute any medical device that is unapproved or which
has a biological, chemical or physical property that may cause an unaccept-
able human health risk.
28
(E) A person shall not distribute any medical device that is not labeled with the
identity of the product and, if appropriate, its ingredients, the name and
address of the manufacturer/sponsor, all indications relating to use of the
device, all relevant warnings, precautions and contraindications, and such
other information as required by the regulatory control authority.
(F) A person shall not distribute any medical device if the product labeling or
advertising is false or misleading.
Section 6
Premarket Evaluation Requirements
(A) Before offering a new medical device for sale, the manufacturer/sponsor
shall submit an application to the regulatory control authority or a surrogate
accredited review entity, and obtain market approval from the authority or
accredited review entity before any sale can occur. To ensure an unbiased,
objective and qualified review, the authority will assign review responsibil-
ity for an application to scientists, clinical experts and/or other officials who
do not have any conflict of interest concerning the medical device.
(B) The regulatory control authority may establish different investigational and
premarket requirements based upon the complexity and risk of the medical
device.
(1) To assure that the scientific and clinical investigations performed by the
manufacturer/sponsor are appropriate to enable a decision by the regu-
latory control authority or review entity on a medical device, it is im-
perative that the authority elucidate in its instructions to manufactur-
ers/sponsors what information is required in premarket applications.
(2) The regulatory control authority or accredited review entity shall use
whatever means of communicating premarket application requirements
to manufacturers/sponsors are deemed to be the most effective and ap-
propriate. These can include regulations, guidelines, policies, points-to-
consider documents, presentations at industry meetings and consulta-
tive discussions between the authority and manufacturers/sponsors about
individual medical devices.
(C) During the investigational phase of product development, the regulatory
control authority or accredited review entity may vary the requirements for
different types of medical devices and will permit researchers and manufac-
turers/sponsors the flexibility to develop new devices provided that human
subjects are adequately protected.
29
(D) The manufacturer/sponsor shall collect information for the premarket ap-
plication during the investigational phase.
(E) Premarket testing can encompass the following: physical and animal tests,
non-clinical laboratory studies and clinical trials.
(F) Manufacturers/sponsors shall conduct investigational tests in accordance
with scientifically sound protocols and procedures, in addition to good labo-
ratory practices (GLPs) in the case of non-clinical laboratory studies.
(G) With respect to clinical research, the manufacturer/sponsor shall inform all
human subjects that the medical device being tested is investigational and
the nature of the risks involved with its use, obtain patients’ written consent
prior to the medical procedure and have safeguards that are in accordance
with the Declaration of Helsinki and other international accords to protect
human subjects.
(H) The manufacturer/sponsor is responsible for and shall assure that all infor-
mation and data generated from investigational studies are accurate, com-
prehensive and thoroughly analyzed.
(I) The manufacturer/sponsor shall submit a premarket application to the regu-
latory control authority or another entity duly authorized by the regulatory
control authority that includes all relevant data from preclinical laboratory,
animal and clinical research, in addition to proposed product labeling that
includes clinical indications, directions for use, warnings, precautions and
contraindications and/or demonstration of conformance with applicable
product standards.
(J) The regulatory control authority and all accredited review entities shall have
procedures to evaluate the safety, effectiveness and quality of new medical
devices as a condition to granting market approval to a manufacturer/spon-
sor.
(K) The manufacturer/sponsor bears the burden of proof in the premarket appli-
cation to demonstrate to the regulatory control authority or an accredited
review entity that a medical device is safe and effective, is manufactured in
accordance with quality standards and its benefits outweigh the risks asso-
ciated with its use.
(L) The regulatory control authority or accredited review entity will determine
within a specified period of time whether to grant market approval to the
manufacturer/sponsor who submits a premarket application.
(M) Upon completion of its review of a premarket application, the regulatory
control authority or accredited review entity shall notify the manufacturer/
sponsor of its decision with respect to:
(1) market approval, in addition to any marketing conditions; or
30
(2) denial of market approval, the basis for the decision and the procedures
the manufacturer/sponsor may follow to appeal the decision of the regu-
latory control authority or surrogate review entity.
(N) In addition to other requirements, the manufacturer/sponsor of any medical
device subject to approval shall comply with such additional requirements
that apply to the product which the regulatory control authority may deem
necessary.
Section 7
Emergency Orders By Regulatory Control Authority Inspectors
(A) If during an inspection of a facility, a regulatory control authority inspector

observes a violation that involves a failure on the part of the manufacturer/
sponsor or other business entity to obtain market approval, or involves a
product that poses a risk of harm to health, or a serious violation of good
manufacturing practices, or is otherwise a serious violation of applicable
laws and regulations, the inspector is authorized to order one or more of the
following actions:
(1) shutdown of the facility;
(2) detention of medical device(s);
(3) physical destruction of medical device(s);
(4) termination of all shipments of medical devices until the regulatory con-
trol authority reauthorizes distribution.
(B) An emergency order by an inspector shall be approved by a supervisor within
a specified period of time and shall remain in effect for a specified period of
time pending further action as described in Section 8.
Section 8
Enforcement of Requirements
(A) The regulatory control authority is authorized to initiate the following ac-
tions against persons or medical devices:
(1) detention or seizure of the medical device(s);
(2) physical destruction of the medical device(s);
(3) recall of the medical device(s);
31
(4) ordering of the responsible person to perform corrective actions in or-

der to bring the medical device(s) into conformity with applicable laws
and regulations, including the provision of new or remedial parts to all
customers or users of the product;
(5) banning of the medical device(s) if it/they cannot be corrected in a man-
ner that insures product safety and effectiveness;
(6) dissemination of a public warning to health professionals, consumers/
patients or other users of the medical device(s).
(7) ordering a change in the medical device(s), including its/their manufac-
turing methods, labeling, advertising or use.
(B) Following initiation of any or all of the actions specified in (B), the person
responsible for the medical device(s) against which the order is directed
shall have the right to submit written information and/or request a meeting
with regulatory control authority officials to discuss the order(s) and ex-
plain why the directed actions may not be necessary.
(C) With respect to actions against persons who violate the law and regulations:
(1) The regulatory control authority may:
(a) revoke or limit the person’s registration;
(b) initiate an administrative proceeding for civil money penalties;
(c) initiate a court action for criminal prosecution of the person, includ-
ing any other individuals responsible for the violation; or
(d) debar the person, including any other individuals responsible for
the violation, from future dealings with the medical devices or with
the regulatory control authority.
(2) With respect to procedures for actions against persons, the following
applies:
(a) Except in cases of emergency, the regulatory control authority shall
first issue a warning letter to the person(s) responsible for the viola-
tion or who have control of the violative medical devices. The warn-
ing letter shall describe the violation and offer the responsible
person(s) an opportunity to comply voluntarily with the law.
(b) Absent voluntary compliance in a timely manner and to the satisfac-
tion of the regulatory control authority, regulatory control authority
officials may initiate further action(s) against the person(s), as de-
scribed below.
32
(c) The person(s) against whom the action(s) is/are directed shall have
the right to submit written information and/or meet with regulatory
control officials to discuss the proposed actions, or request a hearing
before an administrative judge if the person(s) can demonstrate the
existence of a substantial issue of material fact to be presented at the
hearing. If the regulatory control authority provides for a hearing,
the matter shall be assigned to the administrative judge for hearing
and decision.
Section 9
Regulations
(A) The regulatory control authority may promulgate regulations on medical

devices, persons or the authority’s procedures in order to administer and
enforce this law. Regulations may pertain to medical device safety, effective-
ness, performance/quality, good manufacturing practices, good laboratory
practices, premarket testing, labeling, advertising and other such matters
where the regulatory control authority deems that such action is in the in-
terest of public health protection.
(B) With respect to procedures for issuing regulations, the following applies.
(1) The regulatory control authority shall offer proposed regulations to the
public for comment, along with any supporting information.
(2) After evaluating public comments, the regulatory control authority shall
issue a final regulation accompanied by an explanation of the comments
and their disposition by the authority.
(3) In any regulation proceeding, the regulatory control authority may hold
a public meeting, convene an advisory committee or use other proce-
dures to facilitate and expand public participation and/or to improve the
information that is germane to the subject of the regulation(s).
Section 10
Cooperation With Other Governments
The regulatory control authority is authorized to cooperate with other gov-

ernment authorities by sharing information and entering into agreements for the
purpose of the safety, effectiveness and quality of medical devices and the safe
use of such products.
33
Section 11
Public Participation
(A) The regulatory control authority shall periodically issue a Health Register
that contains the authority’s proposed and final regulations, guidelines, op-
erational policies and procedures and other information relevant to the
authority’s regulation of medical devices.
(B) The regulatory control authority shall make available to the public, upon
request, a copy of this law, the implementing regulations, the Health Regis-
ter, a list of all registrations and the public files of all regulation proceed-
ings.
(C) Any member of the public may petition the regulatory control authority to
issue a regulation or to initiate other action.
Section 12
Confidentiality of Information
Officers and employees of the regulatory control authority shall not make
public or use for their own personal gain any trade secret or proprietary infor-
mation which they obtain or become familiar with during the course of their
official duties.
34
Reuse of Medical Devices SECTION III
SECTION III
Reuse of Medical Devices
35
36
REUSE OF MEDICAL DEVICES

One the most controversial and widely debated phenomena that has occurred
during the evolution of the galaxy of medical devices has been the emergence of
“single-use” (sometimes also referred to as “disposable”) devices. The onerous
and time-consuming task of cleaning, repackaging and autoclaving medical de-
vices composed of glass, metal and other durable materials has to a large degree
given way to the convenience of products that can be discarded after one-time
use, especially in industrialized nations of the world that are large consumers of
health care goods.
But convenience has translated into increased costs to hospitals and other
device user facilities, prompting many to reuse these devices several times on
the same or different patients also as a means to contain costs. This may be
particularly endemic in countries where medical equipment procurement re-
sources are scarce. While anecdotal information suggests that device reuse is
widespread, the actual extent of the practice and the magnitude of the risk to
patients have not been firmly characterized.
This lack of information about reuse has led to questions about the inherent
safety of multiple uses of single-use products. For example, are the people who
reprocess disposable devices adequately trained to do so and do they conscien-
tiously follow reprocessing methodologies and protocols, assuming any exist?
Do the sterilants commonly used pose a health risk to patients and are commer-
cially-available disinfection and germicidal agents effective for all types of plas-
tics, ceramics and other materials used in device manufacturing—in other words,
do they cause degradation of devices after multiple reprocessing cycles? Also, if
devices are improperly reprocessed for reuse, are patients at increased risk of
being unwittingly subjected to re-infection or cross-infection, e.g., HIV, Hepati-
tis-B?
Questions have also been raised as to the integrity, functional performance
and clinical effectiveness of reused devices. These concerns have led many to
challenge the ethics of treating patients, often without warning or consent, with
reused devices that most manufacturers label and commercially distribute for
single-use only. Hand in hand with the ethical considerations are issues of legal
liability in terms of who bears primary responsibility for the safety and effective-
ness of a product once it has been reused contrary to its single-use directions. In
many legal systems, once reuse occurs, liability in part or in whole is shifted
from the manufacturer of the original device to the owner or reprocessor of the
reused device. Reuse of single-use devices may also invalidate product warran-
ties.
37
Nevertheless, the desire for cost containment often overrides these concerns,
as does word-of-mouth acceptance of the practice if it does not pose any immedi-
ate or obvious adverse health effects. A case in point is the large-scale reuse of
dialyzers used in hemodialysis. There is abundant evidence of product reuse.
Given the difficulty in tracing problems, such as pyrogenic reactions, to reuse
can be problematic given the poor health status of the majority of dialysis pa-
tients. Indeed, some health care providers have come to accept dialyzer reuse
and the trade-offs that come with it as the standard of care. While questions are
persistently raised about the effects of repeated reprocessing on dialyzer mem-
branes and their functionality compared to new dialyzers, the practice of dia-
lyzer reuse (and reuse of ancillary equipment such as blood lines) has become
increasingly popularized.
In more recent years, these concerns have spawned a rapidly-growing cot-
tage industry of device reprocessors and refurbishers which is minimally regu-
lated. As a result, customers essentially have no independent assurance of either
the firms’ business integrity or the end-safety of the devices they commercially
reprocess for reuse. Thus, caveat emptor (“let the buyer beware”) is the watch-
word.
Despite the rising trend in device reuse, most government regulatory authori-
ties have not offered their approval, either tacitly or explicitly, to this practice. In
fact, just the opposite is true. For example, among the nations that comprise the
European Union, none has policies supporting the practice and some expressly
forbid it by law. The Australian Therapeutic Goods Administration has taken a
position against reuse and proposes to go a step farther by mandating informed
consent prior to the use of a reprocessed device.
Historically, in the United States, the Food and Drug Administration has taken
the position that the health institution or practitioner that authorizes reprocess-
ing and reuse assumes full responsibility for product safety and effectiveness.
This position has changed with FDA’s publication of its Enforcement Priorities
Guidance on Reuse of Single-Use Devices in August 2000. This final guidance
requires premarket clearance depending on certain device risks. Thus, all
reprocessors, including hospitals, will be subject to premarket requirements af-
ter a phase-in period that is to end in August 2002. Additionally, reprocessors
must comply by August 2001 with certain post-market requirements including
inspections, mandatory adverse event reporting, manufacturer registration, prod-
uct listing, labeling, etc.
Although PAHO/WHO neither condone or disfavor reuse, both organizations
recognize the economic realities faced by many Member States and the poten-
tial—real or perceived—for appreciable health care resource-savings that may
accrue from this practice. At the same time, PAHO/WHO believes that as medical
institutions make individual decisions about whether to reuse medical devices,
consideration of possible impacts on patient safety is paramount.
38
In this regard, several fundamental questions must be asked.

• Is adequate medical and scientific information available to determine
the safety and clinical effectiveness or specific reused disposable medi-
cal devices?
• Are there established methods for reprocessing (i.e., cleaning, disinfect-
ing and re-sterilizing) single-use medical devices for reuse and for vali-
dating the integrity of devices reprocessed for reuse?
• What level of sterility is desired?
• What level of product function is desired or acceptable?
• Is information available to identify and exclude specific devices and/or
composition materials from being reused?
• Is information available to determine the appropriate frequency and/or
duration of device reuse?
• What level of surveillance of product quality is necessary to avoid prod-
uct failure and prevent patient harm?
• In the absence of substantiated evidence of any health risk associated
with device reuse, should health care providers be encouraged or com-
pelled to obtain patient informed consent prior to medical treatment
involving reused devices?
These are complex issues that do not lend themselves to clear cut or easy
answers. Ideally, resolution is best achieved by striking a proper balance be-
tween the benefits of reuse (viewed mainly as economic) with all identifiable
risks. In the end, as stated previously, the decision whether or not to reuse medi-
cal devices is one that, in most cases, cannot be made by government authorities.
Rather, it is one that individual health care practitioners and/or medical institu-
tions must make for themselves in tandem with their patients in the light of
current risk-benefit and cost-benefit circumstances.
What role then should national health authorities assume with respect to
advising their citizens on the appropriateness of medical device reuse? PAHO/
WHO believes it is important for health authorities to keep abreast of develop-
ments, both scientific and policy, with relevance to device reuse. They should
also serve as conduits through which international documents and advisories on
this subject can be channeled to local health care communities. As a starting
point, PAHO/WHO is presently aware of the documents listed below that address
the issues of medical device reprocessing and reuse and offer them as useful
references.
39
General Reuse
1. Association for the Advancement of Medical Instrumentation (US):
“Designing, Testing and Labeling Reusable Devices for Reprocessing in Health
Care Facilities - A Guide for Device Manufacturers.”
2. Association for the Advancement of Medical Instrumentation/American
National Standards Institute (US): “Sterilization of Health Care Products -
Requirements for Validation and Routine Control/Industrial Moist Heat
Sterilization.”
3. Association for the Advancement of Medical Instrumentation/American
National Standards Institute (US): “Sterilization of Health Care Products -
Requirements for Validation and Routine Control/Radiation Sterilization.”
4. Canadian Healthcare Association: “The Reuse of Single-Use Medical Devices
- Guidelines for Health Care Facilities.”
5. European Confederation of Medical Devices Associations: “The Case Against
Reuse of Single-Use Medical Devices.”
6. Medical Devices Agency (UK): “The Reuse of Medical Devices Supplied for
Single-Use Only.”
7. National Health and Medical Research Council Expert Panel on Reuse of
Medical Devices Labelled As Single Use (DRAFT).
8. ECRI (US): “Special Report - Reuse of Single-Use Medical Devices: Making
Informed Decisions.”
9. Food and Drug Administration (US): “Enforcement Priorities Guidance on
Reuse of Single-Use Devices.”
Product-Specific
1. American Society of Gastrointestinal Endoscopy/Society of Gastroenterology
Nurses and Associates (US): “Reprocessing of Flexible Gastrointestinal
Endoscopes.”
2. American Society for Testing and Materials (US): “Standard Practice for
Cleaning and Disinfection of Flexible Fiberoptic and Video Endoscopes Used
in the Examination of the Hollow Viscera.”
3. Association for Professionals in Infection Control and Epidemiology (US);
“APIC Guideline for Infection Prevention and Control in Flexible Endoscopy.”
40
4. International Organization for Standardization: “Retrieval and Analysis of

Implantable Medical Devices.”
5. Quebec Ministry of Health (Canada): The Reuse of Single-Use Catheters.”
41
42
Human Subjects Protection Guidelines and Rules APPENDIX
APPENDIX
Human Subjects Protection
Guidelines and Rules
43
44
DECLARATION OF HELSINKI:
RECOMMENDATION GUIDING PHYSICIANS
IN BIOMEDICAL RESEARCH INVOLVING
HUMAN SUBJECTS
Introduction
It is the mission of the physician to safeguard the health of the people. His or
her knowledge and conscience are dedicated to the fulfillment of this mission.
The Declaration of Geneva of the World Medical Assembly binds the physi-
cian with the words, “The health of my patient will be my first consideration,”
and the International Code of Medical Ethics declares that, “A physician shall act
only in the patient’s interest when providing medical care which might have the
effect of weaking the physical and mental condition of the patient.”
The purpose of biomedical research involving human subjects must be to
improve diagnostic, therapeutic and prophylactic procedures and the understand-
ing of the aetiology and pathogenesis of disease.
In current medical practice most diagnostic, therapeutic or prophylactic pro-
cedures involve hazards. This applies especially to biomedical research.
Medical progress is based on research which ultimately must rest in part on
experimentation involving human subjects.
In the field of biomedical research, a fundamental distinction must be recog-
nized between medical research in which the aim is essentially diagnostic or
therapeutic for a patient, and medical research, the essential object of which is
purely scientific and without implying direct diagnostic or therapeutic value to
the person subjected to the research.
Special caution must be exercised in the conduct of research which may
affect the environment, and the welfare of animals used for research must be
respected.
Because it is essential that results of laboratory experiments be applied to
human beings to further scientific knowledge and to help suffering humanity,
the World Medical Association has prepared the following recommendations as
a guide to every physician in biomedical research involving human subjects.
45
They should be kept under review in the future. It must be stressed that the
standards as drafted are only a guide to physicians all over the world. Physi-
cians are not relieved from criminal, civil and ethical responsibilities under the
laws of their own countries.
I. Basic Principles
1. Biomedical research involving human subjects must conform to generally
accepted scientific principles and should be based on adequately performed
laboratory and animal experimentation and on a thorough knowledge of the
scientific literature.
2. The design and performance of each experimental procedure involving hu-
man subjects should be clearly formulated in an experimental protocol which
should be transmitted for consideration, comment and guidance to a spe-
cially appointed committee independent of the investigator are the sponsor,
provided that this independent committee is in conformity with the laws
and regulations of the country in which the research experiment is per-
formed.
3. Biomedical research involving human subjects should be conducted only
by scientifically qualified persons and under supervision of a clinically com-
petent medical person. The responsibility for the human subject must al-
ways rest with a medically qualified person and never on the subject of the
research, even though the subject has given his or her consent.
4. Biomedical research involving human subjects cannot legitimately be car-
ried out unless the importance of the objective is in proportion to the inher-
ent risk to the subject.
5. Every biomedical research project involving human subjects should be pre-
ceded by careful assessment of predictable risks in comparison with fore-
seeable benefits to the subject or to others. Concern for the interests of the
subject must always prevail over the interests of science and society.
6. The right of the research subject to safeguard his or her integrity must al-
ways be respected. Every precaution should be taken to respect the privacy
of the subject and to minimize the impact of the study on the subject’s physi-
cal and mental integrity and on the personality of the subject.
7. Physicians should abstain from engaging in research projects involving hu-
man subjects unless they are satisfied that the hazards involved are believed
to be predictable. Physicians should cease any investigation if the hazards
are found to outweigh the potential benefits.
46
8. In publication of the results of his or her research, the physican is obliged to

preserve the accuracy of the results. Documents of experimentation not in
accordance with the principles laid down in this Declaration should not be
accepted for publication.
9. In any research on human beings, each potential subject must be adequately
informed of the aims, methods, anticipated benefits and potential hazards
of the study and the discomfort it may entail. He or she should be informed
that he or she is at liberty to abstain from participation in the study and that
he or she is free to withdraw his or her consent to participation at any time.
The physician should then obtain the subject’s freely-given informed con-
sent, preferably in writing.
10. When obtaining informed consent for the research project, the physician
should be particularly cautious if the subject is in a dependent relationship
to him or her or may consent under duress. In that case, the informed con-
sent should be a physician who is not engaged in the investigation and who
is completely independent of this official relationship.
11. In case of legal incompetence, informed consent should be obtained from
the legal guardian in accordance with national legislation. Where physical
or mental incapacity makes it impossible to obtain informed consent, or
when the subject is a minor, permission from the responsible relative re-
places that of the subject in accordance with national legislation.
Whenever the minor child is in fact able to give a consent, the minor’s con-
sent must be obtained in addition to the consent of the minor’s legal guard-
ian.
12. The research protocol should always contain a statement of the ethical con-
sideration involved and should indicate that the principles enunciated in
the present Declaration are complied with.
II. Medical Research Combined With

Clinical Care (Clinical Research)
1. In the treatment of the sick person, the physician must be free to use a new
diagnostic and therapeutic measure, if in his or her judgement it offers hope
of saving life, re-establishing health or alleviating suffering.
2. The potential benefits, hazards and discomfort of a new method should be
weighed against the advantages of the best current diagnostic and therapeu-
tic methods.
47
3. In any medical study, every patient, including those of a control group, if

any, should be assured of the best proven diagnostic and therapeutic method.
4. The refusal of the patient to participate in a study must never interfere with
the physician-patient relationship.
5. If the physician considers it essential not to obtain informed consent, the
specific reasons for this proprosal should be stated in the experimental pro-
tocol for transmission to the independent committee.
6. The physician can combine medical research with professional care, the
objective being the acquisition of new medical knowledge, only to the ex-
tent that medical research is justified by its potential diagnostic or thera-
peutic value for the patient.
III. Non-Therapeutic Biomedical Research

Involving Human Subjects (Non-Clinical
Biomedical Research)
1. In the purely scientific application of medical research carried out on a
human being, it is the duty of the physican to remain the protector of the life
and health of that of that person on whom biomedical research is being
carried out.
2. The subjects should be volunteers, either healthy persons or patients for
whom the experimental design is not related to the patient’s illness.
3. The investigator or the investigating team should discontinue the research
if in his/her or their judgement it may, if continued, be harmful to the indi-
vidual.
4. In research on man, the interest of science and society should never take
precedence over considerations related to the well-being of the subject.
48
THE NUREMBERG CODE

1. The voluntary consent of the human subject is absolutely essential.
This means that the person involved should have legal capacity to give con-
sent; should be so situated as to be able to exercise free power of choice,
without the intervention of any element of force, fraud, deceit, duress, over-
reaching or other ulterior form of constraint or coercion; and should have
sufficient knowledge and comprehension of the elements of the subject matter
involved as to enable him to make an understanding and enlightened deci-
sion. This latter element requires that before the acceptance of an affirma-
tive decision by the experimental subject there should be made known to
him the nature, duration and purpose of the experiment; the method and
means by which it is to be conducted; all incoveniences and hazards rea-
sonably to be expected; and the effects upon his health or person which may
possibly come from his participation in the experiment.
The duty and responsibility for ascertaining the quality of the consent rests
upon each individual who initiates, directs or engages in the experiment. It
is a personal duty and responsibility which may not be delegated to another
with impunity.
2. The experiment should be such as to yield fruitful results for the good of
society, unprocurable by other methods or means of study, and not random
and unnecessary in nature.
3. The experiment should be so designed and based on the results of animal
experimentation and a knowledge of the natural history of the disease or
other problem under study that the anticipated results will justify the per-
formance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physi-
cal and mental suffering and injury.
5. No experiment should be conducted where there is an a priori reason to
believe that death or disabling injury will occur, except perhaps in those
experiments where the experimental physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the
humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to pro-
tect the experimental subject against even remote possibilities of injury, dis-
ability or death.
49
8. The experiment should be conducted only by scientifically qualified per-

sons.
The highest degree of skill and care should be required through all stages of
the experiment of those who conduct or engage in the experiment.
9. During the course of the experiment the human subject should be at liberty
to bring the experiment to an end if he has reached the physical or mental
state where continuation of the experiment seemed to him to be impossible.
10. During the course of the experiment the scientist in charge must be pre-
pared to terminate the experiment at any stage, if he has probable [sic] cause
to believe, in the exercise of the good faith, superior skill and careful judge-
ment required of him that a continuation of the experiment is likely to result
in injury, disability or death to the experimental subject.
50
THE BELMONT REPORT
Ethical Principles and Guidelines for

Research Involving Human Subjects
Scientific research has produced substantial social benefits. It has also posed
some troubling ethical questions. Public attention was drawn to these questions
by reported abuses of human subjects in biomedical experiments, especially
during the Second World War. During the Nuremberg War Crime Trials, the
Nuremberg Code was drafted as a set of standards for judging physicians and
scientists who had conducted biomedical experiments on concentration camp
prisoners. This Code became the prototype of many later codes¹ intended to
assure that research involving human subjects would be carried out in an ethical
manner.
The codes consist of rules, some general, others specific, that guide the in-
vestigators or the reviewers of research in their work. Such rules often are inad-
equate to cover complex situations; at times they come into conflict, and they are
frequently difficult to interpret or apply. Broader ethical principles will provide
a basis on which specific rules may be formulated, criticized and interpreted.
Three principles, or general prescriptive judgments, that are relevant to re-
search involving human subjects are identified in this statement. Other prin-
ciples may also be relevant. These three are comprehensive, however, and are
stated at a level of generalization that should assist scientists, subjects, review-
ers and interested citizens to understand the ethical issues inherent in research
involving human subjects. These principles cannot always be applied so as to
resolve beyond dispute particular ethical problems. The objective is to provide
an analytical framework that will guide the resolution of ethical problems aris-
ing from research involving human subjects.
¹ Since 1945, various codes for the proper and responsible conduct of human experimentation in medical research
have been adopted by different organizations. The best known of these codes are the Nuremberg Code of 1947, the
Helsinki Declaration of 1964 (revised in 1975) and the 1971 Guidelines (codified into Federal Regulations in
1974) issued by the former U.S. Department of Health, Education, and Welfare (now the Department of Health
and Human Services). Codes for the conduct of social and behavioral research have also been adopted, the best known
being that of the American Psychological Association, published in 1973.
51
This statement consists of a distinction between research and practice, a dis-

cussion of the three basic ethical principles and remarks about the application of
these principles.
A. Boundaries Between
Practice and Research
It is important to distinguish between biomedical and behavioral research,
on the one hand, and the practice of accepted therapy on the other, in order to
know what activities ought to undergo review for the protection of human sub-
jects of research.
The distinction between research and practice is blurred partly because both
often occur together (as in research designed to evaluate a therapy) and partly
because notable departures from standard practice are often called “experimen-
tal” when the terms “experimental” and “research” are not carefully defined.
For the most part, the term “practice” refers to interventions that are designed
solely to enhance the well-being of an individual patient or client and that have
a reasonable expectation of success. The purpose of medical or behavioral prac-
tice is to provide “diagnosis”, preventive treatment or therapy to particular indi-
viduals.² By contrast, the term “research” designates an activity designed to test
a hypothesis, permit conclusions to be drawn and thereby to develop or contrib-
ute to generalizable knowledge (expressed, for example, in theories, principles
and statements of relationships). Research is usually described in a formal pro-
tocol that sets forth an objective and a set of procedures designed to reach that
objective.
When a clinician departs in a significant way from standard or accepted prac-
tice, the innovation does not, in and of itself, constitute research. The fact that a
procedure is “experimental,” in the sense of new, untested or different, does not
automatically place it in the category of research. Radically new procedures of
²Although practice usually involves interventions designed solely to enhance the well-being of a particular indi-
vidual, interventions are sometimes applied to one individual for the enhancement of the well-being of another (e.g.,
blood donation, skin grafts, organ transplants) or an intervention may have the dual purpose of enhancing the well-
being of a particular individual, and, at the same time, providing some benefit to others (e.g., vaccination, which
protects both the person who is vaccinated and society generally). The fact that some forms of practice have elements
other than immediate benefit to the individual receiving an intervention, however, should not confuse the general
distinction between research and practice. Even when a procedure applied in practice may benefit some other person,
it remains in intervention designed to enhance the well-being of a particular individual or groups of individuals;
thus, it is practice and need not be reviewed as research.
52
this description should, however, be made the object of formal research at an

early stage in order to determine whether they are safe end effective. Thus, it is
the responsibility of medical practice committees, for example, to insist that a
major innovation be incorporated into a formal research project.³
Research and practice may be carried on together when research is designed
to evaluate the safety and efficacy of a therapy. This need not cause any confu-
sion regarding whether or not the activity requires review; the general rule is
that if there is any element of research in an activity, that activity should un-
dergo review for the protection of human subjects.
B. Basic Ethical Principles

The expression “basic ethical principles” refers to those general judgments
that serve as a basic justification for the many particular ethical prescriptions
and evaluations of human actions. Three basic principles, among those gener-
ally accepted in our cultural tradition, are particularly relevant to the ethics of
research involving human subjects: the principles of respect for persons, benefi-
cence and justice.
1. Respect for Persons

Respect for persons incorporates at least two ethical convictions: first, that
individuals should be treated as autonomous agents; and second, that persons
with diminished autonomy are entitled to protection. The principle of respect
for persons thus divides into two separate moral requirements: the requirement
to acknowledge autonomy and the requirement to protect those with diminished
autonomy.
An autonomous person is an individual capable of deliberation about per-
sonal goals and of acting under the direction of such deliberation. To respect
autonomy is to give weight to autonomous persons’ considered opinions and
choices while refraining from obstructing their actions unless they are clearly
detrimental to others. To show lack of respect for an autonomous agent is to
repudiate that person’s considered judgments, to deny an individual the free-
dom to act on those considered judgments, or to withhold information necessary
to make a considered judgment when, there are no compelling reasons to do so.
³Because the problems related to social experimentation may differ substantially from those of biomedical and
behavioral research, the Commission specifically declines to make any policy determination regarding such research at
this time. Rather, the Commission believes that the problem ought to be addressed by one of its successor bodies.
53
However, not every human being is capable of self-determination. The ca-

pacity for self-determination matures during an individual’s life, and some indi-
viduals lose this capacity wholly or in part because of illness, mental disability
or circumstances that severely restrict liberty. Respect for the immature and the
incapacitated may require protecting them as they mature or while they are inca-
pacitated.
Some persons are in need of extensive protection, even to the point of ex-
cluding them from activities which may harm them; other persons require little
protection beyond making sure they undertake activities freely and with aware-
ness of possible adverse consequences. The extent of protection afforded should
depend upon the risk of harm and the likelihood of benefit. The judgment that
any individual lacks autonomy should be periodically re-evaluated and will vary
in different situations.
In most cases of research involving human subjects, respect for persons de-
mands that subjects enter into the research voluntarily and with adequate infor-
mation. In some situations, however, application of the principle is not obvious.
The involvement of prisoners as subjects of research provides an instructive
example. On the one hand, it would seem that the principle of respect for per-
sons requires that prisoners not be deprived of the opportunity to volunteer for
research. On the other hand, under prison conditions they may be subtly co-
erced or unduly influenced to engage in research activities for which they would
not otherwise volunteer. Respect for persons would then dictate that prisoners
be protected. Whether to allow prisoners to “volunteer” or to “protect” them
presents a dilemma. Respecting persons, in most hard cases, is often a matter of
balancing competing claims urged by the principle of respect itself.
2. Beneficence
Persons are treated in an ethical manner not only by respecting their deci-
sions and protecting them from harm, but also by making efforts to secure their
well-being. Such treatment falls under the principle of beneficence. The term
“beneficence” is often understood to cover acts of kindness or charity that go
beyond strict obligation. In this document, beneficence is understood in a stron-
ger sense, as an obligation. Two general rules have been formulated as comple-
mentary expressions of beneficent actions in this sense: (1) do not harm; and (2)
maximize possible benefits and minimize possible harms.
The Hippocratic maxim “do no harm” has long been a fundamental principle
of medical ethics. Claude Bernard extended it to the realm of research, saying
that one should not injure one person regardless of the benefits that might come
to others. However, even avoiding harm requires learning what is harmful; and,
in the process of obtaining this information, persons may be exposed to risk of
harm. Further, the Hippocratic Oath requires physicians to benefit their patients
54
“according to their best judgment.” Learning what will in fact benefit may re-
quire exposing persons to risk. The problem posed by these imperatives is to
decide when it is justifiable to seek certain benefits despite the risks involved,
and when the benefits should be foregone because of the risks.
The obligations of beneficence affect both individual investigators and soci-
ety at large because they extend both to particular research projects and to the
entire enterprise of research. In the case of particular projects, investigators and
members of their institutions are obliged to give forethought to the maximiza-
tion of benefits and the reduction of risk that might occur from the research
investigation. In the case of scientific research in general, members of the larger
society are obliged to recognize the longer term benefits and risks that may result
from the improvement of knowledge and from the development of novel medi-
cal, psychotherapeutic and social procedures.
The principle of beneficence often occupies a well-defined justifying role in
many areas of research involving human subjects. An example is found in re-
search involving children. Effective ways of treating childhood diseases and fos-
tering healthy development are benefits that serve to justify research involving
children—even when individual research subjects are not direct beneficiaries.
Research also makes is possible to avoid the harm that may result from the appli-
cation of previously accepted routine practices that on closer investigation turn
out to be dangerous. But the role of the principle of beneficence is not always so
unambiguous. A difficult ethical problem remains, for example, about research
that presents more than minimal risk without immediate prospect of direct ben-
efit to the children involved. Some have argued that such research is inadmissible,
while others have pointed out that this limit would rule out much research prom-
ising great benefit to children in the future. Here again, as with all hard cases,
the different claims covered by the principle of beneficence may come into con-
flict and force difficult choices.
3. Justice
Who ought to receive the benefits of research and bear its burdens? This is a
question of justice in the sense of “fairness in distribution” or “what is deserved.”
An injustice occurs when some benefit to which a person is entitled is denied
without good reason or when some burden is imposed unduly. Another way of
conceiving the principle of justice is that equals ought to be treated equally.
However, this statement requires explication. Who is equal and who is unequal?
What considerations justify departure from equal distribution? Almost all co-
mmentators allow that distinctions based on experience, age, deprivation, com-
petence, merit and position do sometimes constitute criteria justifying differen-
tial treatment for certain purposes. It is necessary, then, to explain in what re-
spects people should be treated equally. There are several widely accepted for-
mulations of just ways to distribute burdens and benefits. Each formulation
55
mentions some relevant property on the basis of which burdens and benefits
should be distributed. These formulations are: (1) to each person an equal share;
(2) to each person according to individual need; (3) to each person according to
individual effort; (4) to each person according to societal contribution; and (5) to
each person according to merit.
Questions of justice have long been associated with social practices such as
punishment, taxation and political representation. Until recently these questions
have not generally been associated with scientific research. However, they are
foreshadowed even in the earliest reflections on the ethics of research involving
human subjects. For example, during the 19th and early 20th centuries, the bur-
dens of serving as research subjects fell largely upon poor ward patients, while
the benefits of improved medical care flowed primarily to private patients. Subse-
quently, the exploitation of unwilling prisoners as research subjects in Nazi con-
centration camps was condemned as a particularly flagrant injustice. In this
country, in the 1940’s, the Tuskegee syphilis study used disadvantaged, rural
black men to study the untreated course of a disease that is by no means con-
fined to that population. These subjects were deprived of demonstrably effec-
tive treatment in order not to interrupt the project, long after such treatment
became generally available.
Against this historical background, it can be seen how conceptions of justice
are relevant to research involving human subjects. For example, the selection of
research subjects needs to be scrutinized in order to determine whether some
classes (e.g., welfare patients, particular racial and ethnic minorities, or persons
confined to institutions) are being systematically selected simply because of their
easy availability, their compromised position or their manipulability, rather than
for reasons directly related to the problem being studied. Finally, whenever re-
search supported by public funds leads to the development of therapeutic de-
vices and procedures, justice demands both that these not provide advantages
only to those who can afford them and that such research should not unduly
involve persons from groups unlikely to be among the beneficiaries of subse-
quent applications of the research.
C. Applications
Applications of the general principles to the conduct of research leads to
consideration of the following requirements: informed consent, risk/benefit as-
sessment and the selection of subjects of research.
1. Informed Consent
Respect for persons requires that subjects, to the degree that they are ca-
pable, be given the opportunity to choose what shall or shall not happen to
56
them. This opportunity is provided when adequate standards for informed con-
sent are satisfied.
While the importance of informed consent is unquestioned, controversy pre-
vails over the nature and possibility of an informed consent. Nonetheless, there
is widespread agreement that the consent process can be analyzed as containing
three elements: information, comprehension and voluntariness.
Information. Most codes of research establish specific items for disclosure
intended to assure that subjects are given sufficient information. These items
generally include: the research procedure, their purposes, risks and anticipated
benefits, alternative procedures (where therapy is involved), and a statement
offering the subject the opportunity to ask questions and to withdraw at any time
from the research. Additional items have been proposed, including how subjects
are selected, the person responsible for the research, etc.
However, a simple listing of items does not answer the question of what the
standard should be for judging how much and what sort of information should
be provided. One standard frequently invoked in medical practice, namely the
information commonly provided by practitioners in the field or in the locale, is
inadequate since research takes place precisely when a common understanding
does not exist. Another standard, currently popular in malpractice law, requires
the practitioner to reveal the information that reasonable persons would wish to
know in order to make a decision regarding their care. This, too, seems insuffi-
cient since the research subject, being in essence a volunteer, may wish to know
considerably more about risks gratuitously undertaken than do patients who
deliver themselves into the hand of a clinician for needed care.
It may be that a standard of “the reasonable volunteer” should be proposed:
the extent and nature of information should be such that persons, knowing that
the procedure is neither necessary for their care nor perhaps fully understood,
can decide whether they wish to participate in the furthering of knowledge. Even
when some direct benefit to them is anticipated, the subjects should understand
clearly the range of risk and the voluntary nature of participation.
A special problem of consent arises where informing subjects of some perti-
nent aspect of the research is likely to impair the validity of the research. In
many cases it is sufficient to indicate to subjects that they are being invited to
participate in research of which some features will not be revealed until the
research is concluded. In all cases of research involving incomplete disclosure,
such research is justified only if it is clear that: (1) incomplete disclosure is truly
necessary to accomplish the goals of the research; (2) there are no undisclosed
risks to subjects that are more than minimal and; (3) there is an adequate plan for
debriefing subjects, when appropriate, and for dissemination of research results
to them. Information about risks should never be withheld for the purpose of
eliciting the cooperation of subjects, and truthful answers should always be given
57
to direct questions about the research. Care should be taken to distinguish cases
in which disclosure would destroy or invalidate the research from cases in which
disclosure would simply inconvenience the investigator.
Comprehension. The manner and context in which information is conveyed
is as important as the information itself. For example, presenting information in
a disorganized and rapid fashion, allowing too little time for consideration or
curtailing opportunities for questioning, all may adversely affect a subject’s abil-
ity to make an informed choice.
Because the subject’s ability to understand is a function of intelligence, ratio-
nality, maturity and language, it is necessary to adapt the presentation of the
information to the subject’s capacities. Investigators are responsible for ascer-
taining that the subject has comprehended the information. While there is al-
ways an obligation to ascertain that the information about risk to subjects is
complete and adequately comprehended, when the risks are more serious, that
obligation increases. On occasion, it may be suitable to give some oral or written
tests of comprehension. Special provision may need to be made when compre-
hension is severely limited—for example, by conditions of immaturity or mental
disability. Each class of subjects that one might consider as incompetent (e.g.,
infants and young children, mentally disabled patients, the terminally ill and
the comatose) should be considered on its own terms. Even for these persons,
however, respect requires giving them the opportunity to choose to the extent
they are able, whether or not to participate in research. The objections of these
subjects to involvement should be honored, unless the research entails provid-
ing them a therapy unavailable elsewhere. Respect for persons also requires
seeking the permission of other parties in order to protect the subjects from harm.
Such persons are thus respected both by acknowledging their own wishes and
by the use of third parties to protect them from harm.
The third parties chosen should be those who are most likely to understand
the incompetent subject’s situation and to act in that person’s best interest. The
person authorized to act on behalf of the subject should be given an opportunity
to observe the research as it proceeds in order to be able to withdraw the subject
from the research if such action appears in the subject’s best interest.
Voluntariness. An agreement to participate in research constitutes a valid
consent only if voluntarily given. This element of informed consent requires
conditions free of coercion and undue influence. Coercion occurs when an overt
threat of harm is intentionally presented by one person to another in order to
obtain compliance. Undue influence, by contrast, occurs through an offer of an
excessive, unwarranted, inappropriate or improper reward or other overture in
order to obtain compliance. Also, inducements that would ordinarily be accept-
able may become undue influences if the subject is especially vulnerable.
58
Unjustifiable pressures usually occur when persons in positions of authority

or commanding influence—especially where possible sanctions are involved—
urge a course of action for a subject. A continuum of such influencing factors
exists, however, and it is impossible to state precisely where justifiable persua-
sion ends and undue influence begins. But undue influence would include ac-
tions such as manipulating a person’s choice through the controlling influence
of a close relative and threatening to withdraw health services to which an indi-
vidual would otherwise be entitled.
2. Assessment of Risks and Benefits

The assessment of risks and benefits requires a careful arrayal of relevant
data, including, in some cases, alternative ways of obtaining the benefits sought
in the research. Thus, the assessment presents both an opportunity and a re-
sponsibility to gather systematic and comprehensive information about proposed
research. For the investigators, it is a means to examine whether the proposed
research is properly designed. For a review committee, it is a method for deter-
mining whether the risks that will be presented to subjects are justified. For
prospective subjects, the assessment will assist the determination whether or
not to participate.
The Nature and Scope of Risks and Benefits. The requirement that research
be justified on the basis of a favorable risk-benefit assessment bears a close rela-
tion to the principle of beneficence, just as the moral requirement that informed
consent be obtained is derived primarily from the principle of respect for per-
sons. The term “risk” refers to a possibility that harm may occur. However, when
expressions such as “small risk” or “high risk” are used, they usually refer (often
ambiguously) both to the chance (probability) of experiencing a harm and the
severity (magnitude) of the envisioned harm. The term “benefit” is used in the
research context to refer to something of positive value related to health or wel-
fare. Unlike “risk,” “benefit” is not a term that expresses probabilities. Risk is
properly contrasted to probability of benefits and benefits are properly contrasted
with harms rather than risks of harm. Accordingly, so-called risk-benefit assess-
ments are concerned with the probabilities and magnitudes of possible harms
and anticipated benefits. Many kinds of possible harms and benefits need to be
taken into account. There are, for example, risks of psychological harm, physical
harm, legal harm, social harm and economic harm and the corresponding ben-
efits. While the most likely types of harms to research subjects are those of psy-
chological or physical pain or injury, other possible kinds should not be over-
looked.
Risks and benefits of research may affect the individual subjects, the families
of the individual subjects and society at large (or special groups of subjects in
society). Previous codes and Federal regulations have required that risks to sub-
59
jects be outweighed by the sum of both the anticipated benefit to the subject, if
any, and the anticipated benefit to society in the form of knowledge to be gained
from the research. In balancing these different elements, the risks and benefits
affecting the immediate research subject will normally carry special weight. On
the other hand, interests other than those of the subject may on some occasions
be sufficient by themselves to justify the risks involved in the research, so long
as the subjects’ rights have been protected. Beneficence thus requires that we
protect against risk of harm to subjects and also that we be concerned about the
loss of the substantial benefits that might be gained from research.
The Systematic Assessment of Risks and Benefits. It is commonly said that
benefits and risks must be “balanced” and shown to be “in a favorable ratio.”
The metaphorical character of these terms draws attention to the difficulty of
making precise judgments. Only on rare occasions will quantitative techniques
be available for the scrutiny of research protocols. However, the idea of system-
atic, non-arbitrary analysis of risks and benefits should be emulated insofar as
possible. This ideal requires those making decisions about the justifiability of
research to be thorough in the accumulation and assessment of information about
all aspects of the research, and to consider alternatives systematically. This pro-
cedure renders the assessment of research more rigorous and precise, while
making communication between review board members and investigators less
subject to misinterpretation, misinformation and conflicting judgments. Thus,
there should first be a determination of the validity of the presuppositions of the
research; then the nature, probability and magnitude of risk should be distin-
guished with as much clarity as possible. The method of ascertaining risks should
be explicit, especially where there is no alternative to the use of such vague
categories as small or slight risk, it should also be determined whether an
investigator’s estimates of the probability of harm or benefits are reasonable, as
judged by known facts or other available studies.
Finally, assessment of the justifiability of research should reflect at least the
following considerations:
(i) Brutal or inhumane treatment of human subjects is never morally justified.
(ii) Risks should be reduced to those necessary to achieve the research objec-
tive. It should be determined whether it is in fact necessary to use human
subjects at all. Risk can perhaps never be entirely eliminated, but it can
often be reduced by careful attention to alternative procedures.
(iii) When research involves significant risk of serious impairment, review
committees should be extraordinarily insistent on the justification of the
risk (looking usually to the likelihood of benefit to the subject—or, in some
rare cases, to the manifest voluntariness of the participation).
60
(iv) When vulnerable populations are involved in research, the appropriateness

of involving them should itself be demonstrated. A number of variables go
into such judgments, including the nature and degree of risk, the condition
of the particular population involved, and the nature and level of the antici-
pated benefits.
(v) Relevant risks and benefits must be thoroughly arrayed in documents and
procedures used in the informed consent process.
3. Selection of Subjects
Just as the principle of respect for persons finds expression in the require-
ments for consent, and the principle of beneficence in risk-benefit assessment,
the principle of justice gives rise to moral requirements that there be fair proce-
dures and outcomes in the selection of research subjects. Justice is relevant to
the selection of subjects of research at two levels: the social and the individual.
Individual justice in the selection of subjects would require that researchers
exhibit fairness: thus, they should not offer potentially beneficial research only
to some patients who are in their favor or select only “undesirable” persons for
risky research. Social justice requires that distinction be drawn between classes
of subjects that ought, and ought not, to participate in any particular kind of
research, based on the ability of members of that class to bear burdens and on
the appropriateness of placing further burdens on already burdened persons.
Thus, it can be considered a matter of social justice that there is an order of
preference in the selection of classes of subjects (e.g., adults before children) and
that some classes of potential subjects (e.g., the institutionalized mentally infirmed
or prisoners) may be involved as research subjects, if at all, only on certain con-
ditions.
Injustice may appear in the selection of subjects, even if individual subjects
are selected fairly by investigators and treated fairly in the course of research.
Thus injustice arises from social, racial, sexual and cultural biases institutional-
ized in society. Thus, even if individual researchers are treating their research
subjects fairly, and even if IRBs are taking care to assure that subjects are se-
lected fairly within a particular institution, unjust social patterns may neverthe-
less appear in the overall distribution of the burdens and benefits of research.
Although individual institutions or investigators may not be able to resolve a
problem that is pervasive in their social setting, they can consider distributive
justice in selecting research subjects.
Some populations, especially institutionalized ones, are already burdened
in many ways by their infirmities and environments. When research is proposed
that involves risks and does not include a therapeutic component, other less
burdened classes of persons should be called upon first to accept these risks of
research, except where the research is directly related to the specific conditions
61
of the class involved. Also, even though public funds for research may often
flow in the same directions as public funds for health care, it seems unfair that
populations dependent on public health care constitute a pool or preferred re-
search subjects if more advantaged populations are likely to be the recipients of
the benefits.
One special instance or injustice results from the involvement of vulnerable
subjects. Certain groups, such as racial minorities, the economically disadvan-
taged, the very sick and the institutionalized may continually be sought as re-
search subjects, owing to their ready availability in settings where research is
conducted. Given their dependent status and their frequently compromised ca-
pacity for free consent, they should be protected against the danger of being
involved in research solely for administrative convenience, or because they are
easy to manipulate as a result of their illness or socioeconomic condition.
62
GLOSSARY
GLOSSARY
Active Implantable. Any medical device that, in order to function, relies on a source of
electrical energy or any other source of power other than that directly generated by the
human body or gravity which is intended to be totally or partially introduced, surgically
or medically, into the human body or by medical intervention into a natural orifice, and
which is intended to remain after the procedure.
Administrative Proceeding. An action or proceeding that occurs in accordance with
established procedures in order to issue, amend or revoke a regulation or order, or to
take or refrain from taking any other form of administrative action against a product or
person.
Advertising. The process by which information about a medical device is made generally
or publicly known, usually to encourage people to buy or use it. Most if not all advertising,
what may include promotional materials, is considered labeling. (See “Labeling”).
Audit. A systematic, independent examination of a manufacturer’s quality system that is
performed at defined intervals and at sufficient frequency to determine: (1) whether
both quality system activities and the results of such activities comply with quality system
procedures; (2) that these procedures are implemented effectively; and (3) that these
procedures are suitable to achieve quality system objectives.
Banning. An established procedure that a regulatory control authority may use to institute
proceedings to ban a medical device intended for human use that presents substantial
deception or an unreasonable and substantial risk of illness or injury which cannot be
corrected or eliminated by labeling or change in labeling.
Biological(s). Any virus, therapeutic serum, toxic, antitoxin, vaccine, blood, blood
component or derivative, allergenic product or analogous product, or arsphenamine or
its derivatives (or any other trivalent organic arsenic compound), applicable to the
prevention, treatment or cure of diseases or injuries in humans.
CE Mark. “Communaute Europeen” (CE) mark is required for all medical devices marketed
in the European Union indicating that they meet common standards of performance and
safety, known as essential requirements.
Civil Money Penalty. A monetary fine levied against a person found to be in violation of
laws and/or companion regulations or other statutes enforced by a regulatory control
authority.
Clinical Trial. A clinical investigation or research study involving one or more human
subjects which generates clinical data to be used to demonstrate the safety and
effectiveness of a medical device.
Commercialization (also Sale). Any distribution of a medical device intended for human
use which is held or offered for sale.
63
Conflict-of-Interest (also Independence). Means to be impartial and free from any real
or perceived commercial or financial interest or other pressures that might compromise
the independence or objectivity of a regulatory control authority in making public health
decisions or taking regulatory action.
Contract Sterilizer. A person who provides a sterilization service for medical devices
manufactured by another person.
Corrective Action. Refers to the repair, modification or adjustment of a violative condition,
or the repair, modification, adjustment, relabeling, removal or destruction of a violative
product.
Criminal Prosecution. A legal action, typically resulting in imprisonment and/or monetary
fines, that is directed against a person to punish past behavior, deter similar behavior in
the future, and obtain future compliance.
Debarment (also Debar). An administrative sanction that a regulatory control authority
can initiate against a person for inappropriate conduct relating to the development or
approval of a medical device application. Debarment prohibits such persons from
submitting or assisting in the submission of any market application for medical devices.
Design Control. An interrelated set of practices and procedures that are incorporated
into the initial design and development process (i.e., a system of checks and balances).
Design control assures a systematic assessment of the design an integral part of
development of a finished medical device. As a result, deficiencies identified in design
input requirements, in addition to discrepancies between proposed designs and
requirements, are made evident and corrected earlier in the development process,
increasing the likelihood that a design transferred to production will result in a medical
device that is appropriate for its intended use.
Detention. An administrative action by which a regulatory control authority requires
imported articles that appear violative under laws it administers to be held intact until
such time as they are brought into compliance or determined to not be subject to applicable
laws, or refused entry if they are not brought into compliance.
Distributor. Any person who furthers the marketing of a medical device from the original
place of manufacture to the person who makes final delivery or sale to the ultimate
consumer or user, but does not repackage or otherwise change the container, wrapper or
labeling of the device, or the device package. This definition encompasses, but is not
limited to, persons engaged in direct sales, mail orders, leasing, distribution of promotional
samples, distribution of demonstration units, and drop shipping. The term “distributor”
excludes brokers or other persons who merely perform a service for a person (other than
the ultimate consumer) who owns a device.
Effectiveness (also Efficacy). Evidence that a medical device produces an intended
clinical effect in a target population, usually from valid scientific research.
Emergency Order. A command or request by a regulatory control authority as a result of
an unexpected occurrence or set of circumstances that threatens public health and
demands immediate attention.
64
GLOSSARY
Establishment. A place of business under one management at one general physical

location at which a medical device is manufactured, assembled, held, stored, packaged
or otherwise processed.
Facility. Any factory, warehouse, store, pharmacy, hospital, carrier, vessel or any other
location or establishment at which a medical device is manufactured, processed, imported,
packed, refurbished, held, distributed, dispensed or sold.
FDA Approval. A generic term applied to an application for premarket approval (PMA)
that has received consent from the United States Food and Drug Administration to place
a medical device into commercial distribution.
Feasibility Study. An initial limited study conducted at the conceptual stage of a medical
device to confirm its design and operating specifications before beginning an extensive
clinical trial.
Global Harmonization Task Force. A multinational consortium formed in 1992 for the
purpose of converging (i.e., harmonizing) national medical device regulatory requirements
among members to improve public health protection practices, facilitate international
trade, promote technological innovation and provide a model for nations with emerging
device regulatory systems. The United States, European Union, Canada, Japan and
Australia are “Founding Members” of the GHTF. (Additional information about the GHTF
can be obtained from its Internet Web site: www.ghtf.org.)
Good Laboratory Practices (GLPs). Regulations that govern the practices used in non-
clinical studies and are intended to ensure the quality and integrity of safety data used to
support applications for medical device research or marketing applications.
Good Manufacturing Practices (GMPs). See Quality Systems.
Guideline. A non-binding document intended to assist persons with the interpretation
of laws and/or regulations.
Implantable. A medical device that is placed into a surgically or naturally formed cavity
of the human body and intended to remain there for a period of 30 days or longer. A
regulatory control authority may, in order to protect the public health, determine that
devices placed in humans for shorter periods of time are also “implantables.”
Importer. Any person who furthers the marketing of a medical device from a foreign
manufacturer to the person who makes the final delivery or sale of the device to the
ultimate consumer or user, but does not repackage or otherwise change the container,
wrapper or labeling of the device, or the device package.
Invasive/Non-Invasive. Means a device or procedure that, by design or intention: (1)
penetrates or pierces the skin or mucous membranes of the body, the ocular cavity or the
urethra; or (2) enters the ear beyond the external auditory canal, the nose beyond the
nares, the mouth beyond the pharynx, the anal canal beyond the rectum or the vagina
beyond the cervical os.
In Vitro Diagnostic Device. Reagents, instruments and systems intended for use in the
diagnosis of disease or other conditions, including a determination of the state of health,
in order to cure, mitigate, treat or prevent disease. Such products are intended for use in
the collection, preparation and examination of specimens taken from the human body.
65
Investigational Device. A medical device that is the object of a clinical investigation to

evaluate safety and effectiveness.
Labeling (also Label). Means all labels and other written, printed or graphic material
that: (1) is affixed to a medical device or any of its containers or wrappers; or (2)
accompanies a medical device. Labeling may include promotional material for a device.
Listing. A notification to a regulatory control authority from a manufacturer, importer,
or specification developer indicating that it manufactures or has developed a type of
medical device or imports a device into the country.
Manufacturer. Any person who designs, manufactures, fabricates, assembles or processes
a finished medical device. The term “manufacturer” also refers to, but is not limited to,
persons who perform the functions of contract sterilization, installation, relabeling,
remanufacturing, repacking or specifications development, in addition to initial
distributors of devices on behalf of foreign entities.
Market Entry Notification (also Premarket Notification). An application submitted to
a regulatory control authority for the purpose of obtaining clearance to commercially
market a new or modified medical device in that jurisdiction.
Medical Device (also General Medical Device). Refers to an instrument, apparatus,
implement, machine, contrivance, implant, in vitro reagent or other similar or related
article, including any component, part or accessory intended for human use, which is:
(1) intended for use in the diagnosis of disease or other conditions, or in the cure,
mitigation, treatment or prevention of disease; or (2) intended to affect the structure or
any function of the body, and does not achieve its primary intended purpose(s) through
chemical action within or on the body, and which is not dependent on being metabolized
to achieve its primary intended purpose(s).
Packer. A person who packages ready-made products that meet the definition of a medical
device and must handle such devices in conformance with good manufacturing practices.
Performance. When a medical device functions as intended in accordance with associated
labeling and is in conformance with applicable technical specifications and relevant
product standards.
Person. Any individual, partnership, corporation, association, scientific or academic
establishment, government agency or organizational unit of a government agency, or any
other legal entity.
Pharmaceuticals [also Drug(s)]. Means: (1) articles intended for use in the diagnosis,
cure, mitigation, treatment or prevention of disease in humans; (2) articles (other than
food) intended to affect the structure or any function of the body; and (3) articles intended
for use as a component of any articles specified in clauses (1) and (2) of this definition.
Physical Destruction. Procedures used to render medical devices unusable, such as
burning, burial, crushing, grinding, etc.
Policy. A principle, plan or course of action pursued by a government, organization or
individual.
66
GLOSSARY
Post-Market Surveillance. A term that some use synonymously with “post-market

vigilance” (see below) while others use the term to refer to a process by which selected
medical devices, whose long-term performance could not feasibly be demonstrated during
the premarket testing stage, require closer scrutiny after marketing, usually by means of
controlled post-market studies, patient registries or other measures.
Post-Market Vigilance. A process used to monitor the clinical performance of medical
devices in actual use.
Premarket Evaluation. A process by which a regulatory control authority or surrogate
accredited review entity reviews a market application leading to a judgment as to whether
the safety and effectiveness of a new medical device has been adequately demonstrated.
Prescription Use. A medical device which, because of a potentiality for harmful effect,
or the method of its use, or the collateral measures necessary to its use, is not safe except
when used under the supervision, or by order, of a practitioner licensed by law and for
which adequate directions for safe use by consumers cannot be developed.
Processor. A person who processes ready-made products that meet the definition of a
medical device and must manufacture medical devices in conformance with good
manufacturing practices. (See “Manufacturer”).
Process Validation. A means to establish, by objective evidence, that a process consistently
produces a result or a medical device that meets its pre-determined specifications.
Public Warning. A communication issued by a manufacturer, distributor, importer,
regulatory control authority or other responsible party to alert users of a medical device
about unforeseen and/or serious problems or risks associated with use of the device.
Quality Systems (also Good Manufacturing Practices). An umbrella term that refers to
procedures that specify general objectives rather than methods associated with the
manufacture, storage, holding, processing and handling of medical devices. These
procedures address the organizational structure, responsibilities, processes and resources
for implementing quality management requirements associated with medical device
manufacturing.
Recall. The removal of a medical device from commercial distribution, or the field
correction of a marketed device, including its labeling and promotional material, or the
notification of risks to users of such a device which a regulatory control authority deems
to be violative of the law(s) it administers and against which it would initiate legal action.
Records. Anything that is written down and preserved as evidence to verify regulatory
compliance by a person and/or conformance of a medical device to national regulatory
requirements. This includes electronic records.
Registration. A required filing with a regulatory control authority to identify the
establishment seeking to market a medical device within the jurisdiction of the authority.
Refurbisher (also Remarketer). Any person who, for the purpose of resale or redistribution,
visually inspects, functionally tests and services medical devices, as may be necessary, to
demonstrate that a device is in good repair and performing all of the functions for which it
67
was designed. This may include cosmetic enhancement of the device and the performance
of prevention maintenance. Refurbishers do not significantly change the performance, safety
specifications or intended use(s) of a finished device.
Regulation. A rule, ordinance or requirement, established, controlled or directed, to assure
consistent interpretation by persons relating to the manufacture, distribution, importation
and processing of medical devices.
Regulatory Control Authority. An entity empowered to act on behalf of a national government
(in most countries, these are departments within or affiliated with the ministry of health) to
ensure that the requirements of medical device laws are properly carried out in that
jurisdiction.
Relabeler. A person who changes the content of the labeling for a medical device from that
supplied by the original manufacturer for distribution under the establishment’s name. A
relabeler does not include establishments that do not change original labeling but merely
add their own name.
Restricted Use. A medical device for which a regulatory control authority has restricted the
sale, distribution or use upon the written or oral authorization of a health practitioner licensed
by law to administer or use the device, or upon such other conditions as the regulatory
control authority may prescribe.
Reuse (also Reprocessing). Refers to use of a medical device more than once on the same or
multiple patients. Action necessary for reuse of a device may include instructions for assembly/
disassembly, on-site sterilization or disinfection, etc. This definition does not apply to the
refurbishing or repair of a device for the purpose of redistribution or resale.
Safety. Means the benefits of a medical device to a patient undergoing medical diagnosis or
treatment outweigh the risks of the product doing harm to the patient.
Seizure. An action by a regulatory control authority to take control of and, if necessary,
remove a medical device from commerce because it is in violation of national laws and/
or regulations.
Sponsor. A person who initiates, but does not conduct a clinical investigation: that is, an
investigational device is administered, dispensed or used under the immediate direction
of another person.
Tracking. A process to ensure that manufacturers of certain medical devices establish a
system to enable them to promptly locate specific devices in commercial distribution.
Tracking information can be used to facilitate notifications and recalls ordered by a
regulatory control authority in cases when devices are determined to pose serious health
risks.
Warning Letter. An official advisory issued to a person that communicates the position
of a regulatory control authority on a matter which, if left uncorrected, could result in
serious health consequences and appropriate enforcement action(s).
68
REFERENCES
REFERENCES
Annual Summary Report 1996 on Basic Medical Equipment Needs In the Newly
Independent States, WHO European Information Service on Medical Supplies;
September 15, 1996.
“Assessing the Efficacy and Safety of Medical Technologies,” Office of Technology
Assessment, United States Congress; OTA-H-75; September 1978.
“Assignment of Agency Component for Review of Premarket Applications,” Federal
Register, Vol. 56, No. 225, United States Department of Health and Human
Services, Food and Drug Administration; November 21, 1991.
“Basic Documents” - Fortieth Edition, World Health Organization; 1994.
Brochure on “Ethics and Professionalism,” International Association of Medical
Equipment Remarketers.
“Clinical Trials: An Introduction,” Kshitij Mohan, Ph.D. and Harold E. Sargent,
Medical Device and Diagnostic Industry; January 1996.
Conference Proceedings - “International Conference on the Reuse of Disposable
Medical Devices In the 1980’s”; March 1984.
“Council Directive Concerning Medical Devices,” Commission of the European
Communities; June 1993.
“Council Directive On the Approximation of the Laws of the Member States Relating to
Active Implantable Medical Devices” (as amended); Commission of the European
Communities; January 1994.
Draft Document: “European Union Study on EU Medical Devices Industry.”
“Enforcement Priorities Guidance on Reuse of Single-Use Devices,” United States Food
and Drug Administration; August 2000.
“Federal Policies and the Medical Devices Industry,” Office of Technology Assessment,
United States Congress; OTA-H-2291; October 1984.
“Final Document On A Review of Selected Medical Device Applications,” Committee for
Clinical Review, United States Food and Drug Administration; March 1993.
Global Harmonization Task Force (Medical Devices), Lisbon, Portugal Meeting; October 8,
1996.
Global Harmonization Task Force Documents:
· “Essential Principles of Safety and Performance of Medical Devices” [SG1-N020R4].
· “Labelling for Medical Devices” [SG1-N009R6].
· “Role of Standards In Assessment of Medical Devices” [SG1-N012R10].
69
· “Minimum Data Set for Manufacturer Reports to the National Competent Authority”
[SG2-N7R1].
· “Guidance on How to Handle Information Concerning Vigilance Reporting Related to

Medical Devices” [SG2-N8R4].
· “Global Medical Devices Vigilance Report” [SG2-N9R5].
· “National Competent Authority Report Criteria” [SG2-N21R8].
· “Manufacturer Trend Reporting on Post-Market Medical Device Associated Adverse

Events” [SG2-N36R4].
· “Adverse Event Reporting Guidance for the Medical Device Manufacturer Or Its
Authorized Representative” [SG-2-N21R8].
· “Guidance on Quality Systems for the Design and Manufacture of Medical Devices”
[SG3-N99-8].
· “Design Control Guidance for Medical Device Manufacturers” [SG3-N99-9].
· “Process Validation Guidance for Medical Device Manufacturers” [SG3-N99-10].
· “Guidelines for Regulatory Auditing of Quality Systems of Medical Device Manufacturers:

Part 1-General Requirements” [SG4-99-28].
· “Audit Language Requirements” [SG4-99-14].
· “Training Requirements for Auditors” [SG4-00-3].
“How FDA Is Causing A Technological Exodus - A Comparative Analysis of Medical

Device Regulation: United States, Europe, Canada and Japan,” Robert Higgs, Ph.D.,
The Independent Institute; February 1995.
“Managing the Medical Arms Race - Innovation and Public Policy In the Medical
Device Industry,” Susan Bartlett Foote, J.D.; 1992.
“Medical Device Industry Fact Book” - 3rd Edition; 1996.
“Medical Device Regulation - Too Early to Assess European System’s Value as Model
for FDA”; Document to the Chairman, Committee on Labor and Human Resources,
United States Senate (GAO/HEHS-96-65); United States General Accounting
Office; March 1996.
“Medical Device Regulation In Australia”; 1995 and 1996 Presentations.
“Medical Devices: A Legislative Plan”; Document of the Study Group on Medical
Devices, United States Department of Health, Education and Welfare; September
1970. “Medical Devices: International Perspectives on Health and Safety,” C.W.D.
Van Gruting, Pharm.D.; 1994.
“Medical Devices In Europe - Reference Documents/Contact Points,” European
Commission - Directorate-General III - Industry; July 1994.
“Medical Device Regulation In the European Union,” Linda R. Horton, J.D.; United States
Food and Drug Administration; September 1995.”
70
REFERENCES
“Medical Technology - Quality Assurance Needs Stronger Management Emphasis and

Higher Priority,” Document to the Chairman, Subcommittee on Oversight and
Investigations, Committee on Energy and Commerce, United States House of
Representatives; United States General Accounting Office; GAO/PEMB-92-10;
February 1992.
“Medical Technology - Quality Assurance Systems and Global Markets,” Document to the
Chairman, Subcommittee on Health and the Environment, Committee on Energy and
Commerce, United States House of Representatives; United States General Accounting
Office; GAO/PEMB-93-15; August 1993.
“Model Product Approval System for Rapidly Emerging Markets,” Health Industry
Manufacturers Association; January 1996.
“New Medical Devices: Invention, Development and Use,” National Academy of
Engineering, Institute of Medicine; 1988.
“Notified Bodies,” Commission of the European Communities; Revision 3; June 1992.
“Proceedings of the First International Conference of Medical Device Regulatory
Authorities,” World Health Organization, Pan American Health Organization,
United States Food and Drug Administration; June 2-6, 1986.
“Proposed Regulatory Requirements for Medical Devices Sold In Canada,” Document
of Working Group #4, Medical Devices Bureau, Environmental Health Directorate,
Health Protection Branch; January 1995.
“Protecting Human Research Subjects: Human Subjects Research Hardbook,” United
States Department of Energy, Office of Health and Environmental Research;
January 1996.
“Regulating Change: The Regulation of Foods, Drugs, Medical Devices and Cosmetics
In the 1990’s; Jonathan C. Peck, J.D., and Kenneth C. Rabin; 1989.
“Regulatory Cooperation: The U.S. Food and Drug Administration’s Agreements With
Other Countries’ Counterparts,” Linda R. Horton, J.D.; 1996.
Sixth Global Medical Devices Conference: Access To Global Markets Through
Balanced Regulation; October 9-10, 1996.
“The Case Against Reuse of Single Use Medical Devices,” European Confederation of
Medical Devices Associations (EUCOMED).
“The Medical Device Industry - Science, Technology and Regulation In A Competitive
Environment,” Norman F. Estrin, Ph.D.; 1990.
“The Principles of Good Clinical Study Design,” Richard P. Chiacchierini, Ph.D.;
January 1994.
“The Reuse of Hemodialyzers: An Assessment of Safety and Potential Savings,” Enis
Banis, M.D., MSc., and Maurice McGregor, M.D.; Conseil _evaluation des
technologies de la sant_ de Quebec.
71
“The Use of Essential Drugs” - Sixth Document of the WHO Expert Committee, World
Health Organization; 1995.
“WHO Pharmaceuticals Newsletter,” No. 11/12 - November/December 1995 and No. 7;
July 1995.
72

Oms-Ops-2001 DM

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Oms-Ops-2001 DM

Uploaded by

Copyright:

Available Formats

A MODEL

ESSENTIAL DRUGS AND TECHNOLOGY PROGRAM

ESSENTIAL DRUGS AND TECHNOLOGY PROGRAM

© Pan American Health Organization, 2001

Design and layout: Matilde Cresswell

Dr. Daniel López-Acuña

FOREWORD ........................................................................................................................................ iii

PREFACE .............................................................................................................................................. vii

NOTE TO USERS OF THE GUIDE ........................................................................................................ ix

APPENDIX - HUMAN SUBJECTS PROTECTION GUIDELINES AND RULES ................................................................. 43

supplant or usurp any ongoing efforts to regulate medical devices in countries

Overzealous regulation can become a barrier to trade and an inhibitor of

Regulation is often at the confluence of competing interests and outside forces.

The effectiveness of any regulatory system with legal underpinnings is af-

Achieving a high level of compliance from establishments subject to require-

Informing the public, broadly defined, involves conveying in understand-

1. Establishment of a procedure for identifying manufacturers (and oth-

Market Entry Notification

Up-to-date records on the identity and physical location of manufacturers,

B. SPECIFIC PROGRAM COMPONENTS

As discussed previously, one of the entry-level steps in building a medical

• distributor, including multiple distributors of the same device (person

ESTABLISHMENT LOCATION (Street Address): CITY:

COUNTRY: ZIP CODE/POSTAL ADDRESS:

AUTHORIZED ESTABLISHMENT CONTACT/POSITION TITLE:

TELEPHONE NO.: FAX NO.: E-MAIL ADDRESS:

ESTABLISHMENT TYPE (Check one):

ORIGINAL EQUIPMENT MANUFACTURER REPACKAGER/RELABELER

DEVICE IDENTIFICATION (Give name, number, other relevant identifier information):

APPROVED BY US FDA APPLICANT ID NO.:

IS THE PRODUCT AN IMPLANTABLE? YES NO

HAS THE PRODUCT BEEN EXPLANTED AND RE-CONDITIONED FOR SALE?YES NO

IF KNOWN, SPECIFY REMAINING PRODUCT LIFE EXPECTANCY: MONTHS YEARS

SIGNATURE OF AUTHORIZED ESTABLISHMENT OFFICIAL DATE

• Guidance on Quality Systems for the Design and Manufacture of

Assessing Device Safety, Efficacy and Performance

The Principles of Quality Clinical Studies

• A study protocol should state a clear purpose: that is, a hypothesis to be

procedures to be validated; estimates of patient outcomes and variables

(2) “Effectiveness” or “efficacy” means a product can be shown by valid sci-

(A) A person (including any manufacturer, importer, distributor or refurbisher)

(E) Any manufacturer, importer, distributor or other business entity covered by

(A) In addition to complying with all other requirements, manufacturers/ spon-

(A) A manufacturer, processor or packer shall manufacture all medical devices

(A) If during an inspection of a facility, a regulatory control authority inspector

(4) ordering of the responsible person to perform corrective actions in or-

(A) The regulatory control authority may promulgate regulations on medical

The regulatory control authority is authorized to cooperate with other gov-

REUSE OF MEDICAL DEVICES

In this regard, several fundamental questions must be asked.

4. International Organization for Standardization: “Retrieval and Analysis of

8. In publication of the results of his or her research, the physican is obliged to

II. Medical Research Combined With

3. In any medical study, every patient, including those of a control group, if

III. Non-Therapeutic Biomedical Research

THE NUREMBERG CODE

8. The experiment should be conducted only by scientifically qualified per-

THE BELMONT REPORT

Ethical Principles and Guidelines for

This statement consists of a distinction between research and practice, a dis-

this description should, however, be made the object of formal research at an

B. Basic Ethical Principles

1. Respect for Persons